bluuebunny/crossref_metadata_2025 huggingface dataset:
Informant-based hearing difficulties and the risk for mild cognitive impairment and dementia
Authors: Vassilaki Maria , Aakre Jeremiah A , Knopman David S , Kremers Walter K , Mielke Michelle M , Geda Yonas E , Machulda Mary M , Al Fakir Razan , Undavalli Chaitanya , Roberts Rosebud O , Petersen Ronald C
Published: July 2019

Background: hearing loss has been associated with mild cognitive impairment (MCI) and dementia. Studies have not assessed whether hearing difficulties (HD) that interfere with daily activities as reported by partners can be a marker for increased risk for cognitive decline and impairment.

Objective: to assess the cross-sectional and longitudinal associations between informant-based HD, which interfere with daily activities and the risk for MCI and dementia.

Methods: the study included 4812 participants without dementia, enrolled in the Mayo Clinic Study of Aging (mean age (SD) 73.7 (9.6) years) with cognitive evaluation and informant-based report on participant’s HD that interfere significantly with daily activities at baseline and for every 15 months. Cox proportional hazards models (utilising time-dependent HD status and age as the time scale) were used to examine HD and the risk for MCI or dementia, and mixed-effects models (allowing for random subject-specific intercepts and slopes) were used to examine the relationship between HD and cognitive decline.

Results: about, 981 participants had HD and 612 (12.7%) had prevalent MCI at baseline; 759 participants developed incident MCI and 273 developed incident dementia. In cognitively unimpaired participants at baseline, those with HD had higher risk for MCI (hazard ratio [HR] = 1.29, 95% confidence interval [CI] (1.10, 1.51), P = 0.002; adjusting for sex, years of education). In participants without dementia, those with HD had higher risk for dementia (HR: 1.39, 95% CI, (1.08–1.79), P = 0.011; adjusting sex and education). In individuals with MCI, HD was associated with modestly greater cognitive decline.

Conclusions: informant-based HD was associated with increased risk for MCI and dementia.
Foraging ecology influences the number of vertebrae in hydrophiine sea snakes
Authors: Hampton Paul M
Published: July 2019

The number of vertebrae in snakes is highly variable both within and among species. Across ophidian taxa, the number of vertebrae has been linked to many aspects of ecology and performance. Herein, I test the hypothesis that variation in the number of vertebrae and the length of the anterior region of sea snakes are associated with foraging ecology. I predicted that sea snakes that invade burrows and crevices for prey would have relatively longer anterior regions as a result of a greater number of vertebrae. Using radiographs, I counted the number of vertebrae between the head and atria and between the atria and cloaca for 22 species of hydrophiine sea snakes. The length between the cranium and atria was positively associated with the frequency of burrowing prey consumed. The number of vertebrae in the pre-atrial region showed a positive association with diet, although the analysis only approached statistical significance. No association was observed between diet and the number of vertebrae between the atria and cloaca, indicating that heart position is constrained with respect to the cloaca. These data indicate that sea snakes specializing on burrowing prey have adapted elongated, anterior regions of the body through an increased number of vertebrae.
Patterns of retrograde axonal degeneration in the visual system
Authors: de Vries-Knoppert Willemien A , Baaijen Johannes C , Petzold Axel
Published: July 2019

Conclusive evidence for existence of acquired retrograde axonal degeneration that is truly trans-synaptic (RTD) has not yet been provided for the human visual system. Convincing data rely on experimental data of lesions to the posterior visual pathways. This study aimed to overcome the limitations of previous human studies, namely pathology to the anterior visual pathways and neurodegenerative co-morbidity. In this prospective, longitudinal cohort retinal optical coherence tomography scans were acquired before and after elective partial temporal lobe resection in 25 patients for intractable epilepsy. Newly developed region of interest-specific, retinotopic areas substantially improved on conventional reported early treatment diabetic retinopathy study (ETDRS) grid-based optical coherence tomography data. Significant inner retinal layer atrophy separated patients with normal visual fields from those who developed a visual field defect. Acquired RTD affected the retinal nerve fibre layer, ganglion cell and inner plexiform layer and stopped at the level of the inner nuclear layer. There were significant correlations between the resected brain tissue volume and the ganglion cell layer region of interest (R = −0.78, P < 0.0001) and ganglion cell inner plexiform layer region of interest (R = −0.65, P = 0.0007). In one patient, damage to the anterior visual pathway resulted in occurrence of microcystic macular oedema as recognized from experimental data. In the remaining 24 patients with true RTD, atrophy rates in the first 3 months were strongly correlated with time from surgery for the ganglion cell layer region of interest (R = −0.74, P < 0.0001) and the ganglion cell inner plexiform layer region of interest (R = −0.51, P < 0.0001). The different time course of atrophy rates observed relate to brain tissue volume resection and suggest that three distinct patterns of retrograde axonal degeneration exist: (i) direct retrograde axonal degeneration; (ii) rapid and self-terminating RTD; and (iii) prolonged RTD representing a ‘penumbra’, which slowly succumbs to molecularly governed spatial cellular stoichiometric relationships. We speculate that the latter could be a promising target for neuroprotection.
Genome-wide association study of cerebral small vessel disease reveals established and novel loci
Authors: Chung Jaeyoon , Marini Sandro , Pera Joanna , Norrving Bo , Jimenez-Conde Jordi , Roquer Jaume , Fernandez-Cadenas Israel , Tirschwell David L , Selim Magdy , Brown Devin L , Silliman Scott L , Worrall Bradford B , Meschia James F , Demel Stacie , Greenberg Steven M , Slowik Agnieszka , Lindgren Arne , Schmidt Reinhold , Traylor Matthew , Sargurupremraj Muralidharan , Tiedt Steffen , Malik Rainer , Debette Stéphanie , Dichgans Martin , Langefeld Carl D , Woo Daniel , Rosand Jonathan , Anderson Christopher D
Published: July 2019

Intracerebral haemorrhage (ICH) and small vessel ischaemic stroke (SVS) are the most severe manifestations of cerebral small vessel disease. In a cross-phenotype genome-wide association analysis, Chung et al. identify two novel associations at 2q33 and 13q34 plus a previously identified locus at 1q22 for non-lobar ICH and SVS risk.
Social Mixing and Clinical Features Linked With Transmission in a Network of Extensively Drug-resistant Tuberculosis Cases in KwaZulu-Natal, South Africa
Authors: Nelson Kristin N , Jenness Samuel M , Mathema Barun , Lopman Benjamin A , Auld Sara C , Shah N Sarita , Brust James C M , Ismail Nazir , Omar Shaheed Vally , Brown Tyler S , Allana Salim , Campbell Angie , Moodley Pravi , Mlisana Koleka , Gandhi Neel R
Published: July 2019

Background

Tuberculosis (TB) is the leading infectious cause of death globally, and drug-resistant TB strains pose a serious threat to controlling the global TB epidemic. The clinical features, locations, and social factors driving transmission in settings with high incidences of drug-resistant TB are poorly understood.

Methods

We measured a network of genomic links using Mycobacterium tuberculosis whole-genome sequences.

Results

Patients with 2–3 months of cough or who spent time in urban locations were more likely to be linked in the network, while patients with sputum smear–positive disease were less likely to be linked than those with smear-negative disease. Associations persisted using different thresholds to define genomic links and irrespective of assumptions about the direction of transmission.

Conclusions

Identifying factors that lead to many transmissions, including contact with urban areas, can suggest settings instrumental in transmission and indicate optimal locations and groups to target with interventions.
Outcomes of Immunocompromised Adults Hospitalized With Laboratory-confirmed Influenza in the United States, 2011–2015
Authors: Collins Jennifer P , Campbell Angela P , Openo Kyle , Farley Monica M , Cummings Charisse Nitura , Hill Mary , Schaffner William , Lindegren Mary Lou , Thomas Ann , Billing Laurie , Bennett Nancy , Spina Nancy , Bargsten Marisa , Lynfield Ruth , Eckel Seth , Ryan Patricia , Yousey-Hindes Kimberly , Herlihy Rachel , Kirley Pam Daily , Garg Shikha , Anderson Evan J
Published: July 2019

Background

Hospitalized immunocompromised (IC) adults with influenza may have worse outcomes than hospitalized non-IC adults.

Methods

We identified adults hospitalized with laboratory-confirmed influenza during 2011–2015 seasons through CDC’s Influenza Hospitalization Surveillance Network. IC patients had human immunodefiency virus (HIV)/AIDS, cancer, stem cell or organ transplantation, nonsteroid immunosuppressive therapy, immunoglobulin deficiency, asplenia, and/or other rare conditions. We compared demographic and clinical characteristics of IC and non-IC adults using descriptive statistics. Multivariable logistic regression and Cox proportional hazards models controlled for confounding by patient demographic characteristics, pre-existing medical conditions, influenza vaccination, and other factors.

Results

Among 35 348 adults, 3633 (10%) were IC; cancer (44%), nonsteroid immunosuppressive therapy (44%), and HIV (18%) were most common. IC patients were more likely than non-IC patients to have received influenza vaccination (53% vs 46%; P < .001), and ~85% of both groups received antivirals. In multivariable analysis, IC adults had higher mortality (adjusted odds ratio [aOR], 1.46; 95% confidence interval [CI], 1.20–1.76). Intensive care was more likely among IC patients 65–79 years (aOR, 1.25; 95% CI, 1.06–1.48) and those >80 years (aOR, 1.35; 95% CI, 1.06–1.73) compared with non-IC patients in those age groups. IC patients were hospitalized longer (adjusted hazard ratio of discharge, 0.86; 95% CI, .83–.88) and more likely to require mechanical ventilation (aOR, 1.19; 95% CI, 1.05–1.36).

Conclusions

Substantial morbidity and mortality occurred among IC adults hospitalized with influenza. Influenza vaccination and antiviral administration could be increased in both IC and non-IC adults.
New opportunities for targeting redox dysregulation in cardiovascular disease
Authors: Bubb Kristen J , Drummond Grant R , Figtree Gemma A
Published: July 2019

Despite substantial promise, the use of antioxidant therapy to improve cardiovascular outcomes has been disappointing. Whilst the fundamental biology supporting their use continues to build, the challenge now is to differentially target dysregulated redox signalling domains and to identify new ways to deliver antioxidant substances. Looking further afield to other disciplines, there is an emerging ‘tool-kit’ containing sophisticated molecular and drug delivery applications. Applying these to the cardiovascular redox field could prove a successful strategy to combat the increasing disease burden. Excessive reactive oxygen species production and protein modifications in the mitochondria has been the target of successful drug development with several positive outcomes emerging in the cardiovascular space, harnessing both improved delivery mechanisms and enhanced understanding of the biological abnormalities. Using this as a blueprint, similar strategies could be applied and expanded upon in other redox-hot-spots, such as the caveolae sub-cellular region, which houses many of the key cardiovascular redox proteins such as NADPH oxidase, endothelial nitric oxide synthase, angiotensin II receptors, and beta adrenoceptors. The expanded tool kit of drug development, including gene and miRNA therapies, nanoparticle technology and micropeptide targeting, can be applied to target dysregulated redox signalling in subcellular compartments of cardiovascular cells. In this review, we consider the opportunities for improving cardiovascular outcomes by utilizing new technology platforms to target subcellular ‘bonfires’ generated by dysregulated redox pathways, to improve clinical outcomes.
ADAMTS16 activates latent TGF-β, accentuating fibrosis and dysfunction of the pressure-overloaded heart
Authors: Yao Yufeng , Hu Changqing , Song Qixue , Li Yong , Da Xingwen , Yu Yubin , Li Hui , Clark Ian M , Chen Qiuyun , Wang Qing K
Published: July 2019

Aims

Cardiac fibrosis is a major cause of heart failure (HF), and mediated by the differentiation of cardiac fibroblasts into myofibroblasts. However, limited tools are available to block cardiac fibrosis. ADAMTS16 is a member of the ADAMTS superfamily of extracellular protease enzymes involved in extracellular matrix (ECM) degradation and remodelling. In this study, we aimed to establish ADAMTS16 as a key regulator of cardiac fibrosis.

Methods and results

Western blot and qRT–PCR analyses demonstrated that ADAMTS16 was significantly up-regulated in mice with transverse aortic constriction (TAC) associated with left ventricular hypertrophy and HF, which was correlated with increased expression of Mmp2, Mmp9, Col1a1, and Col3a1. Overexpression of ADAMTS16 accelerated the AngII-induced activation of cardiac fibroblasts into myofibroblasts. Protein structural analysis and co-immunoprecipitation revealed that ADAMTS16 interacted with the latency-associated peptide (LAP)-transforming growth factor (TGF)-β via a RRFR motif. Overexpression of ADAMTS16 induced the activation of TGF-β in cardiac fibroblasts; however, the effects were blocked by a mutation of the RRFR motif to IIFI, knockdown of Adamts16 expression, or a TGF-β-neutralizing antibody (ΝAb). The RRFR tetrapeptide, but not control IIFI peptide, blocked the interaction between ADAMTS16 and LAP-TGF-β, and accelerated the activation of TGF-β in cardiac fibroblasts. In TAC mice, the RRFR tetrapeptide aggravated cardiac fibrosis and hypertrophy by up-regulation of ECM proteins, activation of TGF-β, and increased SMAD2/SMAD3 signalling, however, the effects were blocked by TGF-β-NAb.

Conclusion

ADAMTS16 promotes cardiac fibrosis, cardiac hypertrophy, and HF by facilitating cardiac fibroblasts activation via interacting with and activating LAP-TGF-β signalling. The RRFR motif of ADAMTS16 disrupts the interaction between ADAMTS16 and LAP-TGF-β, activates TGF-β, and aggravated cardiac fibrosis and hypertrophy. This study identifies a novel regulator of TGF-β signalling and cardiac fibrosis, and provides a new target for the development of therapeutic treatment of cardiac fibrosis and HF.
Plaque burden can be assessed using intravascular optical coherence tomography and a dedicated automated processing algorithm: a comparison study with intravascular ultrasound
Authors: Gerbaud Edouard , Weisz Giora , Tanaka Atsushi , Luu Romain , Osman Hany Ahmed Salaheldin Hussein , Baldwin Grace , Coste Pierre , Cognet Laurent , Waxman Sergio , Zheng Hui , Moses Jeffrey W , Mintz Gary S , Akasaka Takashi , Maehara Akiko , Tearney Guillermo J
Published: July 2019

Aims

Plaque burden (PB) measurement using intravascular optical coherence tomography (IVOCT) is currently thought to be inferior to intravascular ultrasound (IVUS). We developed an automated IVOCT image processing algorithm to enhance the external elastic lamina (EEL) contour. Thus, we investigated the accuracies of standard IVOCT and an IVOCT enhancement algorithm for measuring PB using IVUS as the reference standard.

Methods and results

The EEL-enhancement algorithm combined adaptive attenuation compensation, exponentiation, angular registration, and image averaging using three sequential frames. In two different laboratories with intravascular imaging expertise, PB was quantified on 200 randomized, matched IVOCT and IVUS images by four independent observers. Fibroatheroma, fibrocalcific plaque, fibrous plaque, pathological intimal thickening (PIT), and mixed plaque were included in each set. Pearson’s correlation coefficients between IVUS and standard IVOCT measurements of PB were 0.61, 0.67, 0.76, 0.78, and 0.87 for fibroatheromas, mixed plaques, fibrocalcific plaques, fibrous plaques, and PIT plaques, respectively. Pearson’s correlation coefficients increased to 0.81, 0.83, 0.83, 0.84, and 0.90 when using the EEL-enhanced images (P = 0.003, P = 0.004, P = 0.08, P = 0.12, and P = 0.23, respectively). EEL-enhanced IVOCT analysis was associated with a lower EEL-area measurement absolute error for fibroatheromas, mixed plaques, and all pooled plaques (P = 0.006, P = 0.02, and P < 0.001, respectively). Compared with standard IVOCT, the EEL-enhanced IVOCT images had a higher sensitivity (79% vs. 28%, P < 0.001) and specificity (98% vs. 85%, P = 0.03) for plaques with an IVUS PB ≥70%.

Conclusion

EEL-enhanced IVOCT can be used to reliably measure PB in all types of coronary atherosclerotic lesions, including fibroatheromas and mixed plaques.
Spontaneous coronary artery dissection of the proximal left circumflex artery: a case report
Authors: Pineda Aleksandra , Martin Josh , Puri Aniket , Jahangiri Bijan
Published: July 2019

Background

Spontaneous coronary artery dissection (SCAD) has gained attention as an important cause of acute coronary syndrome and sudden cardiac death (SCD) among women. Management strategies of SCAD differ from those of atherosclerotic disease. There is an elevated risk of complications and suboptimal outcomes in patients with SCAD undergoing percutaneous coronary interventions (PCIs).

Case summary

A 48-year-old woman without any traditional cardiovascular risk factors was admitted with severe central chest pain with associated dyspnoea and diaphoresis. The patient had a strong family history of SCD, affecting three female members in their 40s and 50s. Cardiac troponins were elevated. Coronary angiogram showed moderate to severe stenosis of the proximal circumflex coronary artery. Optical coherence tomography confirmed SCAD with sub-intimal haematoma. Despite significant stenosis in the proximal segment of a relatively large artery, a decision was made not to proceed with PCI. The follow-up angiogram demonstrated normal coronaries. Magnetic resonance imaging of renal arteries showed features suggestive of fibromuscular dysplasia affecting the right renal artery. Subsequent genetic counselling and gene testing were unremarkable.

Discussion

Conservative management of SCAD is recommended because the large majority of SCAD lesions heal naturally, whereas PCI is associated with increased risk of complications and adverse outcomes. Whether SCAD is associated with the sudden death events in our patient’s family remains unclear. It certainly raises concerns as to an inheritable condition. In the absence of post-mortem findings in her family members, we can only speculate about this representing a possible inheritable form of SCAD.
Myocardial protection: a forgotten modality
Authors: Allen Bradley S
Published: July 2019

The goals of a cardiac surgical procedure are both technical excellence and complete protection of cardiac function. Cardioplegia is used almost universally to protect the heart and provide a quiet bloodless field for surgical accuracy. Yet, despite the importance of myocardial protection in cardiac surgery, manuscripts or dedicated sessions at major meetings on this subject have become relatively rare, as though contemporary techniques now make them unnecessary. Nevertheless, septal dysfunction and haemodynamic support (inotropes, intra-aortic balloon pump, assist devices) are common in postoperative patients, indicating that myocardial damage following cardiac surgery is still prevalent with current cardioplegic techniques and solutions. This article first describes why cardiac enzymes and septal function are the ideal markers for determining the adequacy of myocardial protection. It also describes the underappreciated consequences of postoperative cardiac enzyme release or septal dysfunction (which currently occurs in 40–80% of patients) from inadequate protection, and how they directly correlate with early and especially late mortality. Finally, it reviews the various myocardial protection techniques available to provide a detailed understanding of the cardioplegic methods that can be utilized to protect the heart. This will allow surgeons to critically assess their current method of protection and, if needed, make necessary changes to provide their patients with optimal protection.
How Do Women and Men Use Extra Time? Housework and Childcare after the French 35-Hour Workweek Regulation
Authors: Pailhé Ariane , Solaz Anne , Souletie Arthur
Published: July 2019

This paper analyses how and when men and women devote their extra time to childcare and housework by exploiting an exogenous shock in scheduling: the partial implementation of the 35-hour workweek reform in France. Using propensity score matching and the most recent time use survey (INSEE, 2010), we show that time reallocations differ by gender and day of the week. While men dedicate their extra time to performing more housework on weekdays in the form of mainly time-flexible tasks such as repairs or shopping, they do less on weekends. This shift from weekends to weekdays is not observed for women who perform day-to-day tasks that are less transferable. Women spend more time on childcare and reduce multitasking. Overall, task specialization by gender is more pronounced, and this gendered use of similar extra time illustrates that time allocation is not only a question of time availability. In particular, men and women ‘do gender’ at weekends, when performing tasks is more visible to others.
Restitution and adaptation measurements for the estimate of short-term cardiac action potential memory: comparison of five human ventricular models
Authors: Zaniboni Massimiliano , Cacciani Francesca
Published: July 2019

Aims

This computational study refines our recently published pacing protocol to measure short-term memory (STM) of cardiac action potential (AP), and apply it to five numerical models of human ventricular AP.

Methods and results

Several formulations of electrical restitution (ER) have been provided over the years, including standard, beat-to-beat, dynamic, steady-state, which make it difficult to compare results from different studies. We discuss here the notion of dynamic ER (dER) by relating it to its steady-state counterpart, and propose a pacing protocol based on dER to measure STM under periodically varying pacing cycle length (CL). Under high and highly variable-pacing rate, all models develop STM, which can be measured over the entire sequence by means of dER. Short-term memory can also be measured on a beat-to-beat basis by estimating action potential duration (APD) adaptation after clamping CL constant. We visualize STM as a phase shift between action potential (AP) parameters over consecutive cycles of CL oscillations, and show that delay between CL and APD oscillation is nearly constant (around 92 ms) in the five models, despite variability in their intrinsic AP properties.

Conclusion

dER, as we define it and together with other approaches described in the study, provides an univocal way to measure STM under extreme cardiac pacing conditions. Given the relevance of AP memory for repolarization dynamics and stability, STM should be considered, among other usual biomarkers, to validate and tune cardiac AP models. The possibility of extending the method to in vivo cellular and whole organ models can also be profitably explored.
Aerobic anoxygenic phototrophs are highly abundant in hypertrophic and polyhumic waters
Authors: Szabó-Tugyi Nóra , Vörös Lajos , V.-Balogh Katalin , Botta-Dukát Zoltán , Bernát Gábor , Schmera Dénes , Somogyi Boglárka
Published: July 2019

Aerobic anoxygenic phototrophs (AAPs) are a group of photoheterotrophic bacteria common in natural waters. Here, AAP abundance and contribution to total bacterial abundance and biomass were investigated to test whether the trophic status of a lake or content of coloured dissolved organic matter (CDOM) play a role in determining AAP distribution and abundance in shallow inland lakes, with special focus on hypertrophic and polyhumic waters. Twenty-six different shallow lakes in Hungary were monitored. AAP abundance and biomass were determined by epifluorescence microscopy. The lakes exhibit a broad range of CDOM (2–7000 mg Pt L−1) and phytoplankton biomass (2–1200 μg L−1 chlorophyll a concentration). Very high AAP abundance (up to 3 × 107 cells mL−1) was observed in polyhumic and hypertrophic shallow lakes. AAP abundance was influenced by phytoplankton biomass and CDOM content, and these effects were interrelated. As determined, 40 μg L−1 chlorophyll a and 52 mg Pt L−1 CDOM are threshold levels above which these effects have a synergistic relationship. Hence, the observed high AAP abundance in some soda pans is a consequence of combined hypertrophy and high CDOM content. AAP contribution was influenced by total suspended solids (TSS) content: the success of AAP cells could be explained by high TSS levels, which might be explained by the decrease of their selective grazing control.
Fluorescent signals associated with respiratory Complex I revealed conformational changes in the catalytic site
Authors: Verkhovskaya Marina , Belevich Nikolai
Published: July 2019

Fluorescent signals associated with Complex I (NADH:ubiquinone oxidoreductase type I) upon its reduction by NADH without added acceptors and upon NADH:ubiquinone oxidoreduction were studied. Two Complex I-associated redox-dependent signals were observed: with maximum emission at 400 nm (λex = 320 nm) and 526 nm (λex = 450 nm). The 400 nm signal derived from ubiquinol accumulated in Complex I/DDM (n-dodecyl β-D-maltopyranoside) micelles. The 526 nm redox signal unexpectedly derives mainly from FMN (flavin mononucleotide), whose fluorescence in oxidized protein is fully quenched, but arises transiently upon reduction of Complex I by NADH. The paradoxical flare-up of FMN fluorescence is discussed in terms of conformational changes in the catalytic site upon NADH binding. The difficulties in revealing semiquinone fluorescent signal are considered.
Atypical chromosome 22q11.2 deletions are complex rearrangements and have different mechanistic origins
Authors: Vervoort Lisanne , Demaerel Wolfram , Rengifo Laura Y , Odrzywolski Adrian , Vergaelen Elfi , Hestand Matthew S , Breckpot Jeroen , Devriendt Koen , Swillen Ann , McDonald-McGinn Donna M , Fiksinski Ania M , Zinkstok Janneke R , Morrow Bernice E , Heung Tracy , Vorstman Jacob A S , Bassett Anne S , Chow Eva W C , Shashi Vandana ,   International 22q11.2 Brain,   Behavior Consortium, Vermeesch Joris R
Published: July 2019

The majority (99%) of individuals with 22q11.2 deletion syndrome (22q11.2DS) have a deletion that is caused by non-allelic homologous recombination between two of four low copy repeat clusters on chromosome 22q11.2 (LCR22s). However, in a small subset of patients, atypical deletions are observed with at least one deletion breakpoint within unique sequence between the LCR22s. The position of the chromosome breakpoints and the mechanisms driving those atypical deletions remain poorly studied. Our large-scale, whole genome sequencing study of >1500 subjects with 22q11.2DS identified six unrelated individuals with atypical deletions of different types. Using a combination of whole genome sequencing data and fiber-fluorescence in situ hybridization, we mapped the rearranged alleles in these subjects. In four of them, the distal breakpoints mapped within one of the LCR22s and we found that the deletions likely occurred by replication-based mechanisms. Interestingly, in two of them, an inversion probably preceded inter-chromosomal ‘allelic’ homologous recombination between differently oriented LCR22-D alleles. Inversion associated allelic homologous recombination (AHR) may well be a common mechanism driving (atypical) deletions on 22q11.2.
Optimization of Sludge Fermentation for Volatile Fatty Acids Production
Authors: Salamah Sultan K , Randall Andrew A
Published: July 2019

Prefermentation of primary solids can produce volatile fatty acids (VFAs), and operational strategies may affect the propionic acid content. In this study, three prefermenter phases were used to optimize VFAs using three separate strategies. The phases were (i) glycerol (biodiesel by-product) co-fermentation with primary solids, (ii) the effect of mixing energy on the co-fermentation of glycerol and primary solids and (iii) the effect of hydrogen gas addition on the co-fermentation of glycerol and primary solids. The Phase 1 data showed that glycerol increased the VFAs production 1.2× over the possible value from the added glycerol alone (427 mg-COD/l), implying that the glycerol addition stimulated additional fermentation of primary solids. In Phase 2, low mixing energy in glycerol increased the VFAs production by 80% while slightly favoring propionic acid over acetic acid compared to the higher mixing energy. The addition of hydrogen gas in Phase 3 did not increase the VFAs total production but significantly increased the concentration of propionic acid by 41%. All three optimization approaches performed well and were able to increase the VFAs production and/or increase propionic acid concentration relative to acetic acid.
Serum Lipocalin 2 (Neutrophil Gelatinase–Associated Lipocalin) in Relation to Biomarkers of Inflammation and Cardiac Stretch During Activation of the Renin-Angiotensin-Aldosterone System in Human Immunodeficiency Virus
Authors: Bogorodskaya Milana , Fitch Kathleen V , Burdo Tricia H , Maehler Patrick , Easly Rebecca M , Murray Gillian R , Feldpausch Meghan , Adler Gail K , Grinspoon Steven K , Srinivasa Suman
Published: July 2019

Purpose

To evaluate the relationship of lipocalin 2 to inflammation and cardiac injury with increased aldosterone in human immunodeficiency virus (HIV).

Methods

A standardized 6-day low-sodium diet was used to stimulate renin-angiotensin-aldosterone system (RAAS) activation, and serum lipocalin 2 and biomarkers of inflammation and cardiac stretch were assessed among persons with or without HIV.

Results

Lipocalin 2 levels increased with RAAS activation compared with suppression in the HIV group (median level [interquartile range], 71.3 [59.2–99.7] vs 67.0 [51.8–86.3] ng/mL; P = .01). During RAAS activation, lipocalin 2 was related to biomarkers of inflammation (tumor necrosis factor α [P = .007]), monocyte/macrophage activation (soluble CD163 [P = .005] and chemokine [C-C motif] ligand 2 [P = .03]), and markers of cardiac stretch (brain natriuretic peptide [P < .001] and N-terminal fragment of the prohormone brain natriuretic peptide [P = .001]) in HIV.

Conclusion

Lipocalin 2 may be important in modulating aldosterone-induced inflammation, monocyte activation, and cardiac stretch during RAAS activation in HIV.

Clinical Trial Registration

NCT01407237
Hypertension and diabetes mellitus as risk factors for asthma in Korean adults: the Sixth Korea National Health and Nutrition Examination Survey
Authors: Lee Kyung Hee , Lee Hea Shoon
Published: July 2019

Background

Asthma is a chronic inflammatory disease that may associate with other chronic diseases such as hypertension and diabetes. We observed the effects of blood pressure (BP), fasting blood glucose (FBG), haemoglobin A1c (HbA1c) and insulin on asthma in Korean adults.

Methods

Data from 5045 adults were taken from the 2015 Sixth Korea National Health and Nutrition Examination Survey and analysed using a multiple logistic regression model.

Results

By age, the probability of asthma occurrence was 1.02 times higher (adjusted odds ratio [aOR] 1.02 [95% CI 1.01 to 1.03]). Specifically, asthma occurrence was increased in individuals >66 years of age (aOR 2.40 [95% CI 1.22 to 4.72]). The probability of asthma occurrence in females was higher than in males (aOR 1.73 [95% CI 1.02 to 2.84]). Hypertension and systolic blood pressure (SBP) were found to increase the probability of asthma occurrence by 1.43- and 1.03-fold, respectively. Diabetes mellitus (DM) was another factor that increased with the occurrence of asthma (aOR 1.75 [95% CI 1.06 to 3.02]). The probability of asthma occurrence was not increased with the FBG level, whereas HbA1c (aOR 1.38 [95% CI 1.03 to 1.84]) and insulin levels (aOR 1.02 [95% CI 1.01 to 1.04]) were shown to increase the occurrence of asthma.

Conclusions

Age, sex, hypertension, SBP, DM, HbA1c and insulin levels are all factors that may influence the occurrence of asthma in Korean adults. In particular, hypertension and diabetes emerge from the present study as potential associated factors for the development of asthma.
A single amino acid substitution (H451Y) in Leishmania calcium-dependent kinase SCAMK confers high tolerance and resistance to antimony
Authors: Vergnes Baptiste , Gazanion Elodie , Mariac Cédric , Du Manoir Miléna , Sollelis Lauriane , Lopez-Rubio José-Juan , Sterkers Yvon , Bañuls Anne-Laure
Published: July 2019

Background

For almost a century, antimonials have remained the first-line drugs for the treatment of leishmaniasis. However, little is known about their mode of action and clinical resistance mechanisms.

Objectives

We have previously shown that Leishmania nicotinamidase (PNC1) is an essential enzyme for parasite NAD+ homeostasis and virulence in vivo. Here, we found that parasites lacking the pnc1 gene (Δpnc1) are hypersusceptible to the active form of antimony (SbIII) and used these mutant parasites to better understand antimony’s mode of action and the mechanisms leading to resistance.

Methods

SbIII-resistant WT and Δpnc1 parasites were selected in vitro by a stepwise selection method. NAD(H)/NADP(H) dosages and quantitative RT–PCR experiments were performed to explain the susceptibility differences observed between strains. WGS and a marker-free CRISPR/Cas9 base-editing approach were used to identify and validate the role of a new resistance mutation.

Results

NAD+-depleted Δpnc1 parasites were highly susceptible to SbIII and this phenotype could be rescued by NAD+ precursor or trypanothione precursor supplementation. Δpnc1 parasites could become resistant to SbIII by an unknown mechanism. WGS revealed a unique amino acid substitution (H451Y) in an EF-hand domain of an orphan calcium-dependent kinase, recently named SCAMK. When introduced into a WT reference strain by base editing, the H451Y mutation allowed Leishmania parasites to survive at extreme concentrations of SbIII, potentiating the rapid emergence of resistant parasites.

Conclusions

These results establish that Leishmania SCAMK is a new central hub of antimony’s mode of action and resistance development, and uncover the importance of drug tolerance mutations in the evolution of parasite drug resistance.
Natural disasters and trade: the mitigating impact of port substitution
Authors: Hamano Masashige , Vermeulen Wessel N
Published: July 2019

We study the effect of natural disasters on port-level exports. We model the interaction between firms and ports to study how strongly exports from one port are affected by changes in the cost of exporting at neighboring ports. We extend the standard trade model with heterogeneous firms to a multiple port structure where exporting is subject to port specific local transportation costs, port specific fixed export costs and international bilateral trade costs. We show that gravity distortion due to firm heterogeneity is conditional on the comparative advantage at the port level and resulting substitution of exports across ports. We present evidence of the substitution effect using the 2011 Great East Japan Earthquake, indicating that at least 40% of exports was substituted to other ports following the disaster. The substitution effect is the strongest in technology intensive product categories, which suggests an interaction between supply chains and domestic trade costs.
Relational Mechanisms in Complex Contracting: Factors Associated with Private Managers’ Satisfaction with and Commitment to the Contract Relationship
Authors: Chuang Emmeline , McBeath Bowen , Carnochan Sarah , Austin Michael J
Published: July 2019

The complexity of human service delivery means that contracts are often incomplete or contingent. When contracted services or products are complex, relational contracting can function as a critical informal accountability mechanism. This study introduces and tests a conceptual framework of relational processes and organizational factors hypothesized to inform private human service contract outcomes. Data from a 2015 survey of private nonprofit and for-profit human service organizations in five counties are used to examine factors associated with two proximal indicators of success in human service contracting: commitment to and satisfaction with the contract relationship. Findings provide support for our conceptual framework, highlight the multidimensional nature of trust and commitment, and identify key differences in the relational processes associated with commitment and satisfaction to the contract relationship. Communication quality, trust, and flexibility were associated with satisfaction, whereas interdependence, flexibility, and asset specificity were associated with longer-term commitment to the contract relationship. For-profit ownership was associated with lower commitment and satisfaction. Implications for research and practice are discussed.
Cooling flow solutions for the circumgalactic medium
Authors: Stern Jonathan , Fielding Drummond , Faucher-Giguère Claude-André , Quataert Eliot
Published: July 2019

In several models of galaxy formation feedback occurs in cycles or mainly at high redshift. At times and in regions where feedback heating is ineffective, hot gas in the galaxy halo is expected to form a cooling flow, where the gas advects inward on a cooling timescale. Cooling flow solutions can thus be used as a benchmark for observations and simulations to constrain the timing and extent of feedback heating. Using analytic calculations and idealized 3D hydrodynamic simulations, we show that for a given halo mass and cooling function, steady-state cooling flows form a single-parameter family of solutions, while initially hydrostatic gaseous haloes converge on one of these solutions within a cooling time. The solution is thus fully determined once either the mass inflow rate ${\dot{M}}$ or the total halo gas mass are known. In the Milky Way halo, a cooling flow with ${\dot{M}}$ equal to the star formation rate predicts a ratio of the cooling time to the free-fall time of ∼10, similar to some feedback-regulated models. This solution also correctly predicts observed $\rm{O\,{\small VII}}$ and $\rm{O\,{\small VIII}}$ absorption columns, and the gas density profile implied by $\rm{O\,{\small VII}}$ and $\rm{O\,{\small VIII}}$ emission. These results suggest ongoing heating by feedback may be negligible in the inner Milky-Way halo. Extending similar solutions out to the cooling radius however underpredicts observed $\rm{O\,{\small VI}}$ columns around the Milky-Way and around other low-redshift star-forming galaxies. This can be reconciled with the successes of the cooling flow model with either a mechanism which preferentially heats the $\rm{O\,{\small VI}}$-bearing outer halo, or alternatively if $\rm{O\,{\small VI}}$ traces cool photoionized gas beyond the accretion shock. We also demonstrate that the entropy profiles of some of the most relaxed clusters are reasonably well described by a cooling flow solution.
Super-Eddington growth of black holes in the early universe: effects of disc radiation spectra
Authors: Takeo Eishun , Inayoshi Kohei , Ohsuga Ken , Takahashi Hiroyuki R , Mineshige Shin
Published: July 2019

We investigate the properties of accretion flows on to a black hole (BH) with a mass of MBH embedded in an initially uniform gas cloud with a density of n∞ in order to study rapid growth of BHs in the early Universe. In previous work, the conditions required for super-Eddington accretion from outside the Bondi radius were studied by assuming that radiation produced at the vicinity of the central BH has a single power-law spectrum ν−α at $h\nu \ge 13.6\, {\rm eV}$ (α ∼ 1.5). However, radiation spectra surely depend on the BH mass and accretion rate, and determine the efficiency of radiative feedback. Here, we perform two-dimensional multifrequency radiation hydrodynamical simulations taking into account more realistic radiation spectra associated with the properties of nuclear accretion discs. We find that the critical density of gas surrounding the BH, above which transitions to super-Eddington accretion occur, is alleviated for a wide range of masses of seed BHs (10 ≲ MBH/M⊙ ≲ 106) because photoionization for accretion disc spectra are less efficient than those for single power-law spectra with 1 ≲ α ≲ 3. For disc spectra, the transition to super-Eddington is more likely to occur for lower BH masses because the radiation spectra become too hard to ionize the gas. Even when accretion flows are exposed to anisotropic radiation, the effect due to radiation spectra shrinks the ionized region and likely leads to the transition to a wholly neutral accretion phase. Finally, by generalizing our simulation results, we construct a new analytical criterion required for super-Eddington accretion; $(M_{\rm BH}/10^5\, {\rm M}_\odot) (n_{\infty }/10^4\, {\rm cm}^{-3}) \gtrsim 2.4 (\langle \epsilon \rangle /100\, {\rm eV})^{-5/9}$, where 〈ϵ〉 is the mean energy of ionizing radiation from the central BH.
A model for the minimum mass of bound stellar clusters and its dependence on the galactic environment
Authors: Trujillo-Gomez Sebastian , Reina-Campos Marta , Kruijssen J M Diederik
Published: July 2019

We present a simple physical model for the minimum mass of bound stellar clusters as a function of the galactic environment. The model evaluates which parts of a hierarchically clustered star-forming region remain bound given the time-scales for gravitational collapse, star formation, and stellar feedback. We predict the initial cluster mass functions (ICMFs) for a variety of galaxies and we show that these predictions are consistent with observations of the solar neighbourhood and nearby galaxies, including the Large Magellanic Cloud and M31. In these galaxies, the low minimum cluster mass of ∼102 M⊙ is caused by sampling statistics, representing the lowest mass at which massive (feedback-generating) stars are expected to form. At the high gas density and shear found in the Milky Way’s Central Molecular Zone and the nucleus of M82, the model predicts that a mass >102 M⊙ must collapse into a single cluster prior to feedback-driven dispersal, resulting in narrow ICMFs with elevated characteristic masses. We find that the minimum cluster mass is a sensitive probe of star formation physics due to its steep dependence on the star formation efficiency per free-fall time. Finally, we provide predictions for globular cluster (GC) populations, finding a narrow ICMF for dwarf galaxy progenitors at high redshift, which can explain the high specific frequency of GCs at low metallicities observed in Local Group dwarfs like Fornax and WLM. The predicted ICMFs in high-redshift galaxies constitute a critical test of the model, ideally suited for the upcoming generation of telescopes.
Single-phase multiferroics: new materials, phenomena, and physics
Authors: Lu Chengliang , Wu Menghao , Lin Lin , Liu Jun-Ming
Published: July 2019

Multiferroics, where multiple ferroic orders coexist and are intimately coupled, promise novel applications in conceptually new devices on one hand, and on the other hand provide fascinating physics that is distinctly different from the physics of high-TC superconductors and colossal magnetoresistance manganites. In this mini-review, we highlight the recent progress of single-phase multiferroics in the exploration of new materials, efficient roadmaps for functionality enhancement, new phenomena beyond magnetoelectric coupling, and underlying novel physics. In the meantime, a slightly more detailed description is given of several multiferroics with ferrimagnetic orders and double-layered perovskite structure and also of recently emerging 2D multiferroics. Some emergent phenomena such as topological vortex domain structure, non-reciprocal response, and hybrid mechanisms for multiferroicity engineering and magnetoelectric coupling in various types of multiferroics will be briefly reviewed.
Reduction of Opioid Use by Acupuncture in Patients Undergoing Hematopoietic Stem Cell Transplantation: Secondary Analysis of a Randomized, Sham-Controlled Trial
Authors: Deng Gary , Giralt Sergio , Chung David J , Landau Heather , Siman Jonathan , Li Qing S , Lapen Kaitlyn , Mao Jun J
Published: July 2019

Objective

To evaluate acupuncture as a nonpharmacologic intervention for pain management in patients undergoing hematopoietic stem cell transplantation (HSCT).

Methods

Adult patients with multiple myeloma undergoing high-dose melphalan chemotherapy and autologous peripheral blood HSCT were randomized to receive either true (TA) or sham acupuncture (SA) once daily for five days starting on the day after chemotherapy. Use of pain medications and pain scores were assessed at baseline and at days 5, 15, and 30 after transplantation.

Results

Among 60 evaluable subjects, the SA group (vs TA) had greater than five times odds of increasing pain medication use from baseline. Among patients who were opioid nonusers at baseline, all 15 patients in the TA group remained free from opioid use at the end of the study. In contrast, 20% of those in the SA group (four of the 20 patients) started to use opioids after chemotherapy and stem cell infusion (day 5) and 40% (eight of the 20) had become opioid users by day 30 after HSCT (Fisher exact test P = 0.006). Among patients who were taking opioids at baseline, 14% in the TA group vs 10% in the SA group increased opioid intake at day 5, and 21% (TA) vs 30% (SA) at day 30 (P = 0.86).

Conclusions

Acupuncture appears to significantly reduce the need for pain medications during HSCT and the number of post-HSCT opioid users among baseline opioid nonusers. It warrants further studies as an opioid-sparing intervention for pain in HSCT patients.
What is Global Expressivism?
Authors: Simpson Matthew
Published: July 2019

Global expressivism is the radical view that we should never think of any of our language and thought as representing the world. While interesting, global expressivism has not yet been clearly formulated, and its defenders often use unexplained terms of art to characterise their view. I fix this problem by carefully and clearly exploring the different ways in which we can interpret globalism. I reject almost all of them either because they are implausible or because they are bad interpretations of actual globalist views. I then argue that the most promising version of globalism, which we can find in the work of Huw Price, turns out to be completely compatible with the view of so-called ‘local’ expressivists. The debate between globalists and localists is therefore empty: the real interest in this topic lies not in this debate but in whether globalism is true and if so what follows from it.