bluuebunny/crossref_metadata_2025 huggingface dataset:
Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients
Authors: Wu Haodi , Yang Huaxiao , Rhee June-Wha , Zhang Joe Z , Lam Chi Keung , Sallam Karim , Chang Alex C Y , Ma Ning , Lee Jaecheol , Zhang Hao , Blau Helen M , Bers Donald M , Wu Joseph C
Published: May 2019

Aims

Diastolic dysfunction (DD) is common among hypertrophic cardiomyopathy (HCM) patients, causing major morbidity and mortality. However, its cellular mechanisms are not fully understood, and presently there is no effective treatment. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold great potential for investigating the mechanisms underlying DD in HCM and as a platform for drug discovery.

Methods and results

In the present study, beating iPSC-CMs were generated from healthy controls and HCM patients with DD. Micropatterned iPSC-CMs from HCM patients showed impaired diastolic function, as evidenced by prolonged relaxation time, decreased relaxation rate, and shortened diastolic sarcomere length. Ratiometric Ca2+ imaging indicated elevated diastolic [Ca2+]i and abnormal Ca2+ handling in HCM iPSC-CMs, which were exacerbated by β-adrenergic challenge. Combining Ca2+ imaging and traction force microscopy, we observed enhanced myofilament Ca2+ sensitivity (measured as dF/Δ[Ca2+]i) in HCM iPSC-CMs. These results were confirmed with genome-edited isogenic iPSC lines that carry HCM mutations, indicating that cytosolic diastolic Ca2+ overload, slowed [Ca2+]i recycling, and increased myofilament Ca2+ sensitivity, collectively impairing the relaxation of HCM iPSC-CMs. Treatment with partial blockade of Ca2+ or late Na+ current reset diastolic Ca2+ homeostasis, restored diastolic function, and improved long-term survival, suggesting that disturbed Ca2+ signalling is an important cellular pathological mechanism of DD. Further investigation showed increased expression of L-type Ca2+channel (LTCC) and transient receptor potential cation channels (TRPC) in HCM iPSC-CMs compared with control iPSC-CMs, which likely contributed to diastolic [Ca2+]i overload.

Conclusion

In summary, this study recapitulated DD in HCM at the single-cell level, and revealed novel cellular mechanisms and potential therapeutic targets of DD using iPSC-CMs.
A novel medical device coating prevents Staphylococcus aureus biofilm formation on medical device surfaces
Authors: Hogan Siobhan , Kasotakis Emmanouil , Maher Sean , Cavanagh Brenton , O'Gara James P , Pandit Abhay , Keyes Tia E , Devocelle Marc , O'Neill Eoghan
Published: May 2019

Prevention of device related infections due to Staphylococcus aureus biofilms on devices represents a significant challenge. Such infections have recently been shown to be dependent on the coagulation pathway via activation of pro-thrombin and fibrin production. Three direct-thrombin inhibitors, argatroban, hirudin and dabigatran, were examined to determine their effect on preventing S. aureus biofilm on plastic biochip surfaces under shear stress using an in vivo relevant model of infection. Surface functionalization of polyurethane discs via dityrosine covalent crosslinking with hirudin was performed and changes in bacterial density and microscopic appearances determined. The three direct-thrombin inhibitors prevented S. aureus biofilm formation on plasma-coated surfaces treated with these agents. Coating of polyurethane with one of these agents, hirudin, significantly inhibited biofilm formation on the modified surface. These findings reveal the exciting potential for coating biomaterial surfaces with direct thrombin inhibitors to prevent staphylococcal binding and subsequent device-related infections.
Triglyceride-rich lipoprotein binding and uptake by heparan sulfate proteoglycan receptors in a CRISPR/Cas9 library of Hep3B mutants
Authors: Anower-E-Khuda Ferdous , Singh Gagandeep , Deng Yiping , Gordts Philip L S M , Esko Jeffrey D
Published: May 2019

Binding and uptake of triglyceride-rich lipoproteins (TRLs) in mice depend on heparan sulfate and the hepatic proteoglycan, syndecan-1 (SDC1). Alteration of glucosamine N-sulfation by deletion of glucosamine N-deacetylase-N-sulfotransferase 1 (Ndst1) and 2-O-sulfation of uronic acids by deletion of uronyl 2-O-sulfotransferase (Hs2st) led to diminished lipoprotein metabolism, whereas inactivation of glucosaminyl 6-O-sulfotransferase 1 (Hs6st1), which encodes one of the three 6-O-sulfotransferases, had little effect on lipoprotein binding. However, other studies have suggested that 6-O-sulfation may be important for TRL binding and uptake. In order to explain these discrepant findings, we used CRISPR/Cas9 gene editing to create a library of mutants in the human hepatoma cell line, Hep3B. Inactivation of EXT1 encoding the heparan sulfate copolymerase, NDST1 and HS2ST dramatically reduced binding of TRLs. Inactivation of HS6ST1 had no effect, but deletion of HS6ST2 reduced TRL binding. Compounding mutations in HS6ST1 and HS6ST2 did not exacerbate this effect indicating that HS6ST2 is the dominant 6-O-sulfotransferase and that binding of TRLs indeed depends on 6-O-sulfation of glucosamine residues. Uptake studies showed that TRL internalization was also affected in 6-O-sulfation deficient cells. Interestingly, genetic deletion of SDC1 only marginally impacted binding of TRLs but reduced TRL uptake to the same extent as treating the cells with heparin lyases. These findings confirm that SDC1 is the dominant endocytic proteoglycan receptor for TRLs in human Hep3B cells and that binding and uptake of TRLs depend on SDC1 and N- and 2-O-sulfation as well as 6-O-sulfation of heparan sulfate chains catalyzed by HS6ST2.
Rethinking collaboration: developing a learning platform to address under-five mortality in Mpumalanga province, South Africa
Authors: D’Ambruoso Lucia , van der Merwe Maria , Wariri Oghenebrume , Byass Peter , Goosen Gerhard , Kahn Kathleen , Masinga Sparara , Mokoena Victoria , Spies Barry , Tollman Stephen , Witter Sophie , Twine Rhian
Published: May 2019

Following 50 years of apartheid, South Africa introduced visionary health policy committing to the right to health as part of a primary health care (PHC) approach. Implementation is seriously challenged, however, in an often-dysfunctional health system with scarce resources and a complex burden of avoidable mortality persists. Our aim was to develop a process generating evidence of practical relevance on implementation processes among people excluded from access to health systems. Informed by health policy and systems research, we developed a collaborative learning platform in which we worked as co-researchers with health authorities in a rural province. This article reports on the process and insights brought by health systems stakeholders. Evidence gaps on under-five mortality were identified with a provincial Directorate after which we collected quantitative and qualitative data. We applied verbal autopsy to quantify levels, causes and circumstances of deaths and participatory action research to gain community perspectives on the problem and priorities for action. We then re-convened health systems stakeholders to analyse and interpret these data through which several systems issues were identified as contributory to under-five deaths: staff availability and performance; service organization and infrastructure; multiple parallel initiatives; and capacity to address social determinants. Recommendations were developed ranging from immediate low- and no-cost re-organization of services to those where responses from higher levels of the system or outside were required. The process was viewed as acceptable and relevant for an overburdened system operating ‘in the dark’ in the absence of local data. Institutional infrastructure for evidence-based decision-making does not exist in many health systems. We developed a process connecting research evidence on rural health priorities with the means for action and enabled new partnerships between communities, authorities and researchers. Further development is planned to understand potential in deliberative processes for rural PHC.
Severe mtDNA depletion and dependency on catabolic lipid metabolism in DGUOK knockout mice
Authors: Zhou Xiaoshan , Curbo Sophie , Zhao Qian , Krishnan Shuba , Kuiper Raoul , Karlsson Anna
Published: May 2019

Deoxyguanosine kinase (DGUOK) provides guanosine and adenosine nucleotides for mitochondrial DNA (mtDNA) replication, and its deficiency in humans leads to hepatocerebral mtDNA depletion syndrome or to isolated hepatic disease. There are poor treatment options for DGUOK deficiency and the aim of this study was to generate a model for further studies of the disease that could reveal novel treatment strategies. We report a Dguok-deficient mouse strain that, similar to humans, is most severely affected in the liver. The Dguok complete knockout mice (Dguok−/−) were born normal, but began to lose weight at week 6. A change of fur color from black to blueish grey started at week 16 and was complete at week 20. The movements and behavior were indistinguishable compared to wild-type (wt) mice. A decrease of mtDNA copy number occurred in multiple tissues, with the liver being the most severely affected. The mtDNA-encoded protein cytochrome c oxidase was much lower in Dguok−/− liver tissue than in the wt, whereas the expression of the nuclear-encoded succinate dehydrogenase complex subunit A was unaffected. Histopathology showed severe alterations and immunohistochemistry showed signs of both oxidative stress and regeneration in Dguok−/− liver. The subcutaneous fat layer was undetectable in Dguok−/−, which, in addition to gene expression analysis, indicated an altered lipid metabolism. We conclude that Dguok has a major role for the synthesis of deoxyribonucleotides for mtDNA replication particularly in the liver, similar to the human disorder. Our data also show a catabolic lipid metabolism in liver tissue of Dguok−/−.
Motor neurons from ALS patients with mutations in C9ORF72 and SOD1 exhibit distinct transcriptional landscapes
Authors: Wong Ching-On , Venkatachalam Kartik
Published: May 2019

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that culminates in paralysis and death. Here, we present our analyses of publicly available multiOMIC data sets generated using motor neurons from ALS patients and control cohorts. Functional annotation of differentially expressed genes in induced pluripotent stem cell (iPSC)-derived motor neurons generated from patients with mutations in C9ORF72 (C9-ALS) suggests elevated expression of genes that pertain to extracellular matrix (ECM) and cell adhesion, inflammation and TGFβ targets. On the other end of the continuum, we detected diminished expression of genes repressed by quiescence-promoting E2F4/DREAM complex. Proteins whose abundance was significantly altered in C9-ALS neurons faithfully recapitulated the transcriptional aberrations. Importantly, patterns of gene expression in spinal motor neurons dissected from C9-ALS or sporadic ALS patients were highly concordant with each other and with the C9-ALS iPSC neurons. In contrast, motor neurons from patients with mutations in SOD1 exhibited dramatically different signatures. Elevated expression of gene sets such as ECM and cell adhesion genes occurs in C9 and sporadic ALS but not SOD1-ALS. These analyses indicate that despite the similarities in outward manifestations, transcriptional and proteomic signatures in ALS motor neurons can vary significantly depending on the identity of the causal mutations.
Opioid Use Is Associated With Higher Health Care Costs and Emergency Encounters in Inflammatory Bowel Disease
Authors: Alley Kristen , Singla Anand , Afzali Anita
Published: May 2019

Using Truven Health MarketScan Databases, we examined prescription opioid use in patients with inflammatory bowel disease (IBD) and the resultant increase in use of emergency services and rise in healthcare costs among these patients.
Mesenchymal stromal cells in bone marrow express adiponectin and are efficiently targeted by an adiponectin promoter-driven Cre transgene
Authors: Mukohira Hisa , Hara Takahiro , Abe Shinya , Tani-ichi Shizue , Sehara-Fujisawa Atsuko , Nagasawa Takashi , Tobe Kazuyuki , Ikuta Koichi
Published: May 2019

Stromal cells in bone marrow (BM) constitute a specific microenvironment supporting the development and maintenance of hematopoietic cells. Adiponectin is a cytokine secreted by adipocytes. Besides its anti-diabetic and anti-atherogenic roles, adiponectin reportedly regulates the development and function of hematopoietic cells in BM. However, it remains unclear whether mesenchymal stromal cells in BM express adiponectin. Here, we show that PDGFRβ+VCAM-1+ stromal cells express adiponectin. Lineage tracing revealed that a majority of PDGFRβ+VCAM-1+ cells were targeted by an adiponectin promoter-driven Cre (Adipoq-Cre) transgene. Additionally, the Adipoq-Cre transgene targets a minority of osteoblasts at a younger age but larger populations are targeted at an older age. Furthermore, the Adipoq-Cre transgene targets almost all CXCL12-abundant reticular (CAR) cells and most of the stromal cells targeted by the Adipoq-Cre transgene are CAR cells. Finally, deletion of interleukin-7 (IL-7) by the Adipoq-Cre transgene resulted in severe impairment of B lymphopoiesis in BM. These results demonstrate that PDGFRβ+VCAM-1+ stromal cells in BM express adiponectin and are targeted by the Adipoq-Cre transgene, suggesting a broader specificity of the Adipoq-Cre transgene.
ISAba1-dependent overexpression of eptA in clinical strains of Acinetobacter baumannii resistant to colistin
Authors: Potron Anaïs , Vuillemenot Jean-Baptiste , Puja Hélène , Triponney Pauline , Bour Maxime , Valot Benoit , Amara Marlène , Cavalié Laurent , Bernard Christine , Parmeland Laurence , Reibel Florence , Larrouy-Maumus Gerald , Dortet Laurent , Bonnin Rémy A , Plésiat Patrick
Published: May 2019

Background

Colistin resistance in Acinetobacter baumannii often results from mutational activation of the two-component system PmrAB and subsequent addition of phospho-ethanolamine (pEtN) to lipooligosaccharide by up-regulated pEtN transferase PmrC.

Objectives

To characterize mechanisms of colistin resistance independent of PmrCAB in A. baumannii.

Methods

Twenty-seven colistin-resistant A. baumannii were collected from 2012 to 2018. Analysis of operon pmrCAB was performed by PCR and sequencing. Seven strains were investigated further by WGS and whole-genome MLST (wgMLST).

Results

Seven out of the 27 selected isolates were found to overexpress eptA, a gene homologous to pmrC, likely as a consequence of upstream insertion of an ISAba1 element. Insertion sites of ISAba1 were mapped 13, 18 and 156 bp ahead of the start codon of eptA in five strains, one strain and one strain, respectively. The finding that the isolates did not cluster together when compared by wgMLST analysis supports the notion that distinct insertion events occurred in close, but different, genetic backgrounds.

Conclusions

Activation of eptA and subsequent addition of pEtN to the cell surface represents a novel mechanism of resistance to colistin in A. baumannii.
Designing and executing a functional exercise to test a novel informatics tool for mass casualty triage
Authors: Donevant Sara B , Svendsen Erik R , Richter Jane V , Tavakoli Abbas S , Craig Jean B r , Boltin Nicholas D , Valafar Homayoun , DiNardi Salvatore Robert , Culley Joan M
Published: May 2019

Objective

The testing of informatics tools designed for use during mass casualty incidents presents a unique problem as there is no readily available population of victims or identical exposure setting. The purpose of this article is to describe the process of designing, planning, and executing a functional exercise to accomplish the research objective of validating an informatics tool specifically designed to identify and triage victims of irritant gas syndrome agents.

Materials and Methods

During a 3-year time frame, the research team and partners developed the Emergency Department Informatics Computational Tool and planned a functional exercise to test it using medical records data from 298 patients seen in 1 emergency department following a chlorine gas exposure in 2005.

Results

The research team learned valuable lessons throughout the planning process that will assist future researchers with developing a functional exercise to test informatics tools. Key considerations for a functional exercise include contributors, venue, and information technology needs (ie, hardware, software, and data collection methods).

Discussion

Due to the nature of mass casualty incidents, testing informatics tools and technology for these incidents is challenging. Previous studies have shown a functional exercise as a viable option to test informatics tools developed for use during mass casualty incidents.

Conclusion

Utilizing a functional exercise to test new mass casualty management technology and informatics tools involves a painstaking and complex planning process; however, it does allow researchers to address issues inherent in studying informatics tools for mas casualty incidents.
Spatial ecology of river otters in a human-modified landscape
Authors: Hanrahan Alexander T , Rutter Andrew U , Nielsen Clayton K , Schauber Eric M
Published: May 2019

River otter populations have expanded across much of their historical range, including in Illinois where they were reintroduced from 1994 to 1997. These expanding populations are recolonizing a wide range of landscapes with different levels of human modification, which could influence how river otters use space in relation to habitat characteristics and each other. Our objectives were to quantify 1) home ranges and core areas, 2) sociality, and 3) habitat selection across all available habitats and within home ranges (second- and third-order selection, respectively) of 22 radiomarked river otters (Lontra canadensis) in southern Illinois during 2014–2016. Our study area contained a diverse mix of forest, agriculture, aquatic and wetland habitats, and a range of urban development intensity. We examined sociality using the frequency at which individuals were located < 25 m from a conspecific and compared home-range overlap among individuals based on sex. Habitat selection at the second and third order was analyzed using an eigen-analysis of selection ratios based on landcover categories. Similar to other studies, male river otters had > 2-fold larger home ranges and core areas than females in southern Illinois. Several lines of evidence indicated males were more social than females. Males were located close to a conspecific more frequently than were females, and overlap of home ranges and core areas among males was greater than it was among females or between sexes. As observed in other landscapes, river otters strongly selected herbaceous and wooded wetlands at both second- and third-order scales. River otters selected terrestrial cover types with vegetative cover potentially due to shelter or prey availability. Forests were selected over crop fields at the third-order scale, which was consistent with studies using sign surveys. River otters in our study had home ranges containing 0–40% developed land cover, but we found no evidence that otters living in more developed areas used their home ranges more selectively. River otters in this landscape were plastic in regard to social behavior and habitat selection, highlighting their generalist nature and providing insight into their ability to successfully recolonize areas of the Midwest with sufficient vegetative cover and aquatic habitat, among other factors.
Measures of the Degree of Departure from Ignorable Sample Selection
Authors: Little Roderick J A , West Brady T , Boonstra Philip S , Hu Jingwei
Published: May 2019

With the current focus of survey researchers on “big data” that are not selected by probability sampling, measures of the degree of potential sampling bias arising from this nonrandom selection are sorely needed. Existing indices of this degree of departure from probability sampling, like the R-indicator, are based on functions of the propensity of inclusion in the sample, estimated by modeling the inclusion probability as a function of auxiliary variables. These methods are agnostic about the relationship between the inclusion probability and survey outcomes, which is a crucial feature of the problem. We propose a simple index of degree of departure from ignorable sample selection that corrects this deficiency, which we call the standardized measure of unadjusted bias (SMUB). The index is based on normal pattern-mixture models for nonresponse applied to this sample selection problem and is grounded in the model-based framework of nonignorable selection first proposed in the context of nonresponse by Don Rubin in 1976. The index depends on an inestimable parameter that measures the deviation from selection at random, which ranges between the values zero and one. We propose the use of a central value of this parameter, 0.5, for computing a point index, and computing the values of SMUB at zero and one to provide a range of the index in a sensitivity analysis. We also provide a fully Bayesian approach for computing credible intervals for the SMUB, reflecting uncertainty in the values of all of the input parameters. The proposed methods have been implemented in R and are illustrated using real data from the National Survey of Family Growth.
Shale gas Sino-foreign agreements in China: attractive or not?
Authors: Guo (Claire) Nan
Published: May 2019

This article presents an analysis of how China will participate in the ‘shale revolution’ through Sino-foreign collaboration by evaluating the legal arrangements on offer today in the onshore shale gas industry—specifically focusing on the essence of the different agreements, the obstacles for foreign investors under the current petroleum regime, why obstacles exist and what the relevant solutions to them might be. The first part of the article provides a general introduction to the use of JV contracting models and PSCs in the development of Chinese shale projects with foreign investment, and analyses the crucial factors which apply to determining the boundaries between the different forms of contract and the concerns of the relevant parties in the process of negotiation. The second part of the article investigates the reasons for the absence of IOCs in the second shale gas bid round, and why Shell terminated its PSC with CNPC even though commerciality had been declared. Finally, taking into account the underlying reasons for why China's legal regime hinders foreigner investors' enthusiasm for shale gas investment, it proposes relevant suggestions to enhance the attractiveness of Sino-foreign shale gas cooperation.
Rational Requirements and the Primacy of Pressure
Authors: Fogal Daniel
Published: May 2019

There are at least two threads in our thought and talk about rationality, both practical and theoretical. In one sense, to be rational is to respond correctly to the reasons one has. Call this substantive rationality. In another sense, to be rational is to be coherent, or to have the right structural relations hold between one's attitudinal mental states, independently of whether those states are justified. Call this structural rationality. According to the standard view, structural rationality is associated with a distinctive set of requirements that mandate or prohibit certain combinations of attitudes, and it's in virtue of violating these requirements that incoherent agents are irrational. I think the standard view is mistaken. The goal of this paper is to explain why, and to motivate an alternative account: rather than corresponding to a set of law-like requirements, structural rationality should be seen as corresponding to a distinctive kind of pro tanto rational pressure—that is, something that comes in degrees, having both magnitude and direction. Something similar is standardly assumed to be true of substantive rationality. On the resulting picture, each dimension of rational evaluation is associated with a distinct kind of rational pressure—substantive rationality with (what I call) justificatory pressure and structural rationality with attitudinal pressure. The former is generated by one's reasons while the latter is generated by one's attitudes. Requirements turn out to be at best a footnote in the theory of rationality.
SDSS J094635.06+101706.1: a redshift one, very radio-loud, γ-ray emitting narrow-line Seyfert 1 galaxy
Authors: Yao Su , Komossa S , Liu Wen-Juan , Yi Weimin , Yuan Weimin , Zhou Hongyan , Wu Xue-Bing
Published: May 2019

As hybrids of narrow-line Seyfert 1 (NLS1) galaxies and blazars, γ-ray emitting NLS1s are important probes of jet physics in the high Eddington-ratio regime. Only very few of them are known to date; the majority of them below redshift $z$ = 0.5. Here, we present the identification of the γ-ray emitting AGN TXS 0943+105 (SDSS J094635.06+101706.1) as a high-redshift NLS1 galaxy. It turns out to be one of the radio-loudest NLS1s known, highly variable at all wavelengths, and shows widely extended radio emission at a (projected) >100 kpc scale. It is a known strong γ-ray emitter with a luminous flare reported previously. At redshift $z$ = 1.004, this is the most distant γ-NLS1 known to date.
Microhomologies are prevalent at Cas9-induced larger deletions
Authors: Owens Dominic D G , Caulder Adam , Frontera Vincent , Harman Joe R , Allan Alasdair J , Bucakci Akin , Greder Lucas , Codner Gemma F , Hublitz Philip , McHugh Peter J , Teboul Lydia , de Bruijn Marella F T R
Published: May 2019

The CRISPR system is widely used in genome editing for biomedical research. Here, using either dual paired Cas9D10A nickases or paired Cas9 nuclease we characterize unintended larger deletions at on-target sites that frequently evade common genotyping practices. We found that unintended larger deletions are prevalent at multiple distinct loci on different chromosomes, in cultured cells and mouse embryos alike. We observed a high frequency of microhomologies at larger deletion breakpoint junctions, suggesting the involvement of microhomology-mediated end joining in their generation. In populations of edited cells, the distribution of larger deletion sizes is dependent on proximity to sgRNAs and cannot be predicted by microhomology sequences alone.
Organelle Studies and Proteome Analyses of Mitochondria and Plastids Fractions from the Diatom Thalassiosira pseudonana
Authors: Schober Alexander F , R�o B�rtulos Carolina , Bischoff Annsophie , Lepetit Bernard , Gruber Ansgar , Kroth Peter G
Published: May 2019

Diatoms are unicellular algae and evolved by secondary endosymbiosis, a process in which a red alga-like eukaryote was engulfed by a heterotrophic eukaryotic cell. This gave rise to plastids of remarkable complex architecture and ultrastructure that require elaborate protein importing, trafficking, signaling and intracellular cross-talk pathways. Studying both plastids and mitochondria and their distinctive physiological pathways in organello may greatly contribute to our understanding of photosynthesis, mitochondrial respiration and diatom evolution. The isolation of such complex organelles, however, is still demanding, and existing protocols are either limited to a few species (for plastids) or have not been reported for diatoms so far (for mitochondria). In this work, we present the first isolation protocol for mitochondria from the model diatom Thalassiosira pseudonana. Apart from that, we extended the protocol so that it is also applicable for the purification of a high-quality plastids fraction, and provide detailed structural and physiological characterizations of the resulting organelles. Isolated mitochondria were structurally intact, showed clear evidence of mitochondrial respiration, but the fractions still contained residual cell fragments. In contrast, plastid isolates were virtually free of cellular contaminants, featured structurally preserved thylakoids performing electron transport, but lost most of their stromal components as concluded from Western blots and mass spectrometry. Liquid chromatography electrospray-ionization mass spectrometry studies on mitochondria and thylakoids, moreover, allowed detailed proteome analyses which resulted in extensive proteome maps for both plastids and mitochondria thus helping us to broaden our understanding of organelle metabolism and functionality in diatoms.
Self-Administered Acupressure for Chronic Low Back Pain: A Randomized Controlled Pilot Trial
Authors: Murphy Susan Lynn , Harris Richard Edmund , Keshavarzi Nahid Roonizi , Zick Suzanna Maria
Published: May 2019

Objective Chronic low back pain (CLBP) is associated with fatigue, pain, poor sleep, and disability. Acupressure is a low-risk treatment option used to manage symptoms in other groups, but its efficacy, particularly on fatigue and sleep, is unknown in CLBP. This study examined preliminary effects of two types of self-administered acupressure (relaxing and stimulating) on fatigue, pain, sleep, and reported disability.

Methods A randomized pilot trial was conducted (N = 67) in which participants were randomized into six weeks of relaxing acupressure, stimulating acupressure, or usual care. Fatigue was measured by the Brief Fatigue Inventory, pain was measured by the Brief Pain Inventory, sleep was measured by the Pittsburgh Sleep Quality Index, and reported disability was measured by the Roland Morris Scale.

Results Baseline characteristics were similar across groups. An intent-to-treat analysis using general linear models showed positive improvement in pain in acupressure groups compared with usual care. Pain was reduced by 35–36% in the acupressure groups. Improvement in fatigue was also found in stimulating acupressure compared with usual care. Adverse events were minimal and related to application of too much pressure.

Discussion Although this was a small study, acupressure demonstrated promising preliminary support of efficacy for pain and fatigue reduction in this population.
Partisanship vs. Principle: Understanding Public Opinion on Same-Day Registration
Authors: McCarthy Devin
Published: May 2019

Voter access has become a deeply polarized issue in American politics. It is well known that policymakers’ positions on election laws are often dictated by whether they think the laws will help their electoral interests and those of their party. But we know little about whether public opinion on election laws is similarly driven by partisan interest or is instead constrained by concerns of procedural legitimacy. To answer this question, I conduct a survey experiment that frames the issue of same-day registration (SDR) in terms of which major party it is expected to help electorally. The results provide clear evidence that both Democrats and Republicans are less likely to support SDR after being told the policy will primarily increase turnout among voters of the opposing party, but little evidence that being told SDR will benefit their own party affects opinion. These findings suggest an asymmetry in citizens’ willingness to choose partisan interest over democratic principles based on whether they perceive a rule change as benefiting the in-party or out-party.
An Alternative Route to Voting Reform: the Right to Vote, Voter Registration, Redistricting and U.S. State Constitutions
Authors: Martorano Miller Nancy , Hamm Keith E , Aroca Maria , Hedlund Ronald D
Published: May 2019

The U.S. Constitution reserves to states the responsibility for regulating most aspects of elections. Recently, the Supreme Court has weakened the tools for federal officials to challenge state elections practices under the Voting Rights Act and signaled a great deal of deference to state authority over election law. As a result, state legislatures’ latitude to regulate elections is constrained primarily by state constitutions. With voter ID laws and partisan gerrymandering commanding considerable attention in recent years, it is important to investigate the importance of state constitutions in this area. In this article, we discuss recent efforts by voting and election reformers to utilize state constitutions to challenge restrictive voting laws and partisan gerrymandering, whether by enacting state constitutional amendments or relying on state constitutional provisions in state court litigation. We also highlight the diverse and often underappreciated landscape of voting and election laws in the states and the resources available to reformers at the state level by analyzing state constitutional provisions bearing on the right to vote, voter registration, and redistricting.
Boundaries of the Construct of Unemployment in the Preretirement Years: Exploring an Expanded Measurement of Lost-Work Opportunity
Authors: Voss Maren Wright , Al Snih Soham , Li Wei , Hung Man , Richards Lorie Gage
Published: May 2019

There is uncertainty related to whether retirement negatively affects health—possibly due to complexity around retirement decisions. Lost-work opportunity through unemployment or forced retirement has been shown to negatively affect health. Lost-work opportunity can be captured in two measurement fields, either a reported experience of being forced into retirement or reported unemployment. However, 17% of individuals retiring due to the loss of work opportunity identified in qualitative interviewing (i.e., unemployment, temporary lay-offs, company buy-outs, forced relocations, etc.) do not report this unemployment or involuntary retirement in quantitative survey responses. We propose broadening the conceptualization of late-career unemployment to incorporate other lost work opportunity scenarios. Using the Health and Retirement Study (HRS), a lost-work opportunity score (LOS) was computed from items indicating unemployment and forced or unplanned retirement. Correlations were computed between this LOS and all continuous variables in the RAND longitudinal compilation of the HRS to determine its convergent and discriminant validity. The LOS demonstrated a Chronbach’s alpha of α = .82 and had convergent validity with constructs of employment (9 variables), finances (36 variables), and health (14 variables), as predicted by the literature on retirement timing. No other continuous variables in the HRS were identified with a moderate or strong correlation to LOS, demonstrating discriminant validity. Further research should explore whether a combination of variables in the HRS can improve the accuracy of measuring lost-work opportunity. Improved precision in measurement, through an expanded conceptualization of lost-work opportunity, may help explicate the retirement-related factors that affect health, to inform policy and support healthy aging decisions at a societal level.
The close interrelation between colorectal cancer, infection and microbiota
Authors: Massaut Edouard , Hendlisz Barbara , Klastersky Jean A.
Published: May 2019

Purpose of review

Evaluate the recent literature about the relation of clinical infection and colorectal cancer in terms of diagnosis of an occult infection and possible impact on oncological outcome and review the possible role of the gut microbiota in the role of colorectal cancer oncogenesis.

Recent findings

Data published within the 2 last years have been reviewed and the conclusions, mostly supporting previously published information, have been critically discussed.

Infection (bacteremia, cellulitis) might be a surrogate of occult colorectal cancer and postoperative infection complications might jeopardize long-term survival after potentially curative surgery. The role of the gut microbiota in the genesis of colorectal cancer remains an exciting though unresolved question.
Role of Interferon (IFN)α in “Cocktails” for the Generation of (Leukemia-derived) Dendritic Cells (DCleu) From Blasts in Blood From Patients (pts) With Acute Myeloid Leukemia (AML) and the Induction of Antileukemic Reactions
Authors: Hirn Lopez Annika , Deen Diana , Fischer Zuzanna , Rabe Alexander , Ansprenger Christian , Stein Kathy , Vogt Valentin , Schick Julia , Kroell Tanja , Kraemer Doris , Kolb Hans-Jochem , Tischer Johanna , Schmid Christoph , Schmetzer Helga
Published: May 2019

Strategies to stabilize remissions by specific elimination of residual acute myeloid leukemia (AML) blasts are needed. Leukemia-derived dendritic cell (DCleu/DC) generated from myeloid blasts improve antileukemic T-cell reactivity and install T-cell memory. Interferon (IFN)α-DC methods produce DCleu from chronic myeloid leukemia-patients (pts’) blood. Various INFα-containing versus other DC methods were studied to produce DCleu (evaluated by flowcytometry) from AML-pts’ blast-containing mononuclear (MNC) or whole blood (WB). After DCleu/DC stimulation in mixed lymphocyte cultures, T cells’ potential to gain antileukemic cytotoxicity was studied and correlated with different DC methods and DCleu/DC counts. (1) Generation of DCleu/DC: (a) “IFN-GIT” [containing granulocyte macrophage-colony stimulating factor (GM-CSF)+IFNα+ tumor necrosis factor (TNF)-α] produced DC successfully (≥10% DC, ≥5% DCleu/cells) from AML-MNC (WB) in 54 (56%), “MCM-Mimic” in 76 (75%), “Picibanil” in 83 (64%), and “Calcium-ionophore” in 42 (67%) of cases. Proportions of DC subtypes in MNC (WB) were comparable with all DC methods, (b) IFNα combinations containing only GM-CSF+IFNα or only IFNα showed low efficiency to produce DCleu/DC from MNC (WB) compared with “IFN-GIT.” (2) Antileukemic functionality: DCleu/DC-stimulated T cells showed improved leukemia cytotoxicity compared with blast cells or unprimed (“up”) T cells. The highest blast proliferation (=insufficient T cells) was seen with “IFN-GIT” DC-stimulated T cells. Probability to respond to immunotherapy or to obtain blast lysis of DC-stimulated T cells correlated with high proportions of DCleu/DC after DC culture, independent of DC-generating methods. (3) Cytokine release profiles: levels of interleukin-6, IFN-γ, and interleukin-2 were significantly lower in DC culture supernatants (from MNC/WB) with “IFN-GIT” compared with “MCM,” “Pici,” and “Ca” DC supernatants. Our data show that (1) WB culture simulates AML-pts’ in vivo situation, (2) DC generation is possible from AML-MNC (WB) with IFNα-containing and other DC methods, (3) successful IFNα-DC generation needs GM-CSF+IFNα+TNF-α (IFN-GIT); however, “IFN-GIT” produces less DCleu/DC compared with other (non-IFNα) DC methods, (4) T cells stimulated with “IFN-GIT”-produced DCleu/DC yielded comparable antileukemic cytotoxicity; however, in cases without achieved blast lysis, an increased blast proliferation was observed.
Volumetric Absorptive Microsampling: A New Sampling Tool for Therapeutic Drug Monitoring of Antiepileptic Drugs
Authors: D'Urso Annachiara , Rudge James , Patsalos Philip N. , de Grazia Ugo
Published: May 2019

Background:

Volumetric absorptive microsampling (VAMS) is a novel sampling technique for the collection of fixed-volume capillary blood. In this study, a new analytical method was developed and used to quantify 14 different antiepileptic drugs (AEDs) and 2 active metabolites in samples collected by VAMS. These data were compared with concentration measurements in plasma.

Methods:

The authors developed a selective and sensitive liquid chromatography–mass spectrometry (LC-MS/MS) assay to measure the concentrations of several AEDs in whole blood collected by VAMS, which were compared with a commercially available LC-MS/MS kit for AED monitoring in plasma. Drugs and internal standards were extracted from whole blood/plasma samples by a simple protein precipitation.

Results:

An LC-MS/MS method analyzing VAMS samples was successfully developed and validated for the determination of various AED concentrations in whole blood according to EMA guidelines for bioanalytical method validation. Extraction recovery was between 91% and 110%. No matrix effect was found. The method was linear for all drugs with R2 ≥0.989 in all cases. Intra-assay and inter-assay reproducibility analyses demonstrated accuracy and precision within acceptance criteria. Carry over and interferences were negligible. No volumetric HCT% bias was found at 3 different HCT values (35%–55%) with recovery being consistently above 87%. Samples are very stable at temperatures ranging from −20°C to 37°C and for a 4-month period. Leftover EDTA samples from 133 patients were tested to determine concentration differences between plasma and whole blood sampled by VAMS. The resulting difference varied less than 15% apart from those drugs with a blood/plasma ratio (R) different from 1.

Conclusions:

The assay allows for highly sensitive and selective quantification of several AEDs in whole blood samples collected by VAMS. The developed method is accurate and precise and free from matrix effects and volumetric HCT% bias.
Interior Temperature and Relative Humidity of an Envelope During Mail Transport by the Japan Post in the Summer: Preliminary Study for a Stability Test of Dried Blood Spot Samples Sent as Regular Mail
Authors: Mukai Yuji , Minami Rumiko , Doki Kosuke , Inotsume Nobuo , Toda Takaki
Published: May 2019

Background:

The dried blood spot (DBS) is well studied and has been considered a useful technique for collecting biological specimens for therapeutic drug monitoring. Since DBS cards are transported as regular mail, these samples can be exposed to various climatic conditions while in transit. However, there have been limited amounts of data regarding interior temperature and relative humidity (RH) of the envelope during mail transport of DBS samples. This study investigated the interior temperature and RH during the transport of regular mail by Japan Post during the summer and assessed the effect of the gas permeability of zip lock bags on the interior temperature and RH when used as containers for the DBS card.

Methods:

Either an aluminum zip lock bag, gas-impermeable, or a plastic zip lock bag, gas-permeable, containing a desiccant pouch (10 g) and a data logger was packed in an envelope and then transported by mail between Sapporo and Tsukuba/Kagoshima. The ambient temperature and RH in the above cities during the mail transport were obtained from the website of the Japan Meteorological Agency.

Results:

The envelope was exposed to ≥30°C for up to 22 hours during the mail transport. Differences in the temperature between the interior and exterior of the envelope were almost completely within a range of ±4°C regardless of the gas permeability of the zip lock bags. Although the ambient RH was sometimes over 90% during mail transport, the mean interior RHs of the envelope containing the aluminum or plastic zip lock bag throughout the transport process were 13% and 17%, respectively.

Conclusions:

Both zip lock bags provided comparable results in relation to the interior temperature and RH of the envelope. Our results suggest that a stability test at 40°C and 90% RH for at least 24 hours is recommended as a validation process if DBS samples are transported as regular mail in Japan. However, conditions may need to be modified depending on the regions.
Mental illness is associated with more pain and worse functional outcomes after ankle fracture
Authors: Simske Natasha M. , Audet Megan A. , Kim Chang-Yeon , Benedick Alex , Vallier Heather A.
Published: May 2019

Objectives:

To assess clinical and functional outcomes after ankle fracture in patients with preexisting mental illness.

Design:

Retrospective study.

Setting:

Level 1 trauma center.

Patients/Participants:

One thousand three hundred seventy-eight adult patients treated for ankle fractures; 228 (17%) had preexisting mental illness.

Intervention:

Open reduction internal fixation.

Main outcome measure:

Rates of complications and reoperations. Functional outcomes were assessed via Foot Function Index (n = 530) and Short Musculoskeletal Function Assessment (n = 530).

Results:

Depression was the most common mental illness (63%), followed by anxiety (23%). Mental illness was associated with older age, female sex, and preexisting medical comorbidities, including diabetes and obesity. Mental illness was not associated with specific fracture patterns or open injury. Complications occurred no more often in patients with mental illness, but secondary operations (13% vs 7%) were more likely, particularly implant removals (8% vs 4%), both P < .05. Functional outcomes were worse in mentally ill patients as measured by the Foot Function Index (39 vs 30, P = .006) and Short Musculoskeletal Function Assessment Mobility: 45 vs 35, Bothersome: 35 vs 26 and Dysfunction: 35 vs 26, all P < .01.

Conclusion:

Secondary operations were nearly 50% more frequent in patients with mental illness, and functional outcome scores were significantly worse, suggesting that mental illness, unrelated to injury and treatment parameters, has major influence on outcomes. In the future, strategies to identify and treat mental illness prior to and after treatment could improve functional outcomes following ankle fracture.
Resuscitative Strategies to Modulate the Endotheliopathy of Trauma: From Cell to Patient
Authors: Wu Feng , Chipman Amanda , Pati Shibani , Miyasawa Byron , Corash Laurence , Kozar Rosemary A.
Published: May 2019

Clinical data has supported the early use of plasma in high ratios of plasma to red cells to patients in hemorrhagic shock. The benefit from plasma seems to extend beyond its hemostatic effects to include protection to the post-shock dysfunctional endothelium. Resuscitation of the endothelium by plasma and one of its major constituents, fibrinogen, involves cell surface stabilization of syndecan-1, a transmembrane proteoglycan and the protein backbone of the endothelial glycocalyx. The pathogenic role of miRNA-19b to the endothelium is explored along with the PAK-1-mediated intracellular pathway that may link syndecan-1 to cytoskeletal protection. Additionally, clinical studies using fibrinogen and cyroprecipitate to aid in hemostasis of the bleeding patient are reviewed and new data to suggest a role for plasma and its byproducts to treat the dysfunctional endothelium associated with nonbleeding diseases is presented.
Trauma-induced Rejection in Vascularized Composite Allotransplantation
Authors: Etra Joanna W. , Shores Jaimie T. , Sander Inbal B. , Brandacher Gerald , Lee W. P. Andrew
Published: May 2019

Vascularized composite allotransplantation (VCA) is a relatively new field in reconstructive medicine. Likely a result of the unique tissue composition of these allografts—including skin and often a bone marrow component—the immunology and rejection patterns do not always mimic those of the well-studied solid organ transplantations. While the number and type of VCAs performed is rapidly expanding, there is still much to be discovered and understood in the field. With more patients, new findings and patterns emerge and add to our understanding of VCA. Here, we present a case report of an upper extremity transplant recipient with trauma-induced rejection.