Association between low density lipoprotein and rheumatoid arthritis genetic factors with low density lipoprotein levels in rheumatoid arthritis and non-rheumatoid arthritis controls.

Abstract:
OBJECTIVES
While genetic determinants of low density lipoprotein (LDL) cholesterol levels are well characterised in the general population, they are understudied in rheumatoid arthritis (RA). Our objective was to determine the association of established LDL and RA genetic alleles with LDL levels in RA cases compared with non-RA controls.

METHODS
Using data from electronic medical records, we linked validated RA cases and non-RA controls to discarded blood samples. For each individual, we extracted data on: first LDL measurement, age, gender and year of LDL measurement. We genotyped subjects for 11 LDL and 44 non-HLA RA alleles, and calculated RA and LDL genetic risk scores (GRS). We tested the association between each GRS and LDL level using multivariate linear regression models adjusted for age, gender, year of LDL measurement and RA status.

RESULTS
Among 567 RA cases and 979 controls, 80% were female and mean age at the first LDL measurement was 55 years. RA cases had significantly lower mean LDL levels than controls (117.2 vs 125.6 mg/dl, respectively, p<0.0001). Each unit increase in LDL GRS was associated with 0.8 mg/dl higher LDL levels in both RA cases and controls (p=3.0×10(-7)). Each unit increase in RA GRS was associated with 4.3 mg/dl lower LDL levels in both groups (p=0.01).

CONCLUSIONS
LDL alleles were associated with higher LDL levels in RA. RA alleles were associated with lower LDL levels in both RA cases and controls. As RA cases carry more RA alleles, these findings suggest a genetic basis for epidemiological observations of lower LDL levels in RA.

Liao|Katherine P|KP|
Diogo|Dorothée|D|
Cui|Jing|J|
Cai|Tianxi|T|
Okada|Yukinori|Y|
Gainer|Vivian S|VS|
Murphy|Shawn N|SN|
Gupta|Namrata|N|
Mirel|Daniel|D|
Ananthakrishnan|Ashwin N|AN|
Szolovits|Peter|P|
Shaw|Stanley Y|SY|
Raychaudhuri|Soumya|S|
Churchill|Susanne|S|
Kohane|Isaac|I|
Karlson|Elizabeth W|EW|
Plenge|Robert M|RM|

D020022:Genetic Predisposition to Disease

Rheumatoid Arthritis
Gene Polymorphism
Lipids


Provisional in-silico biopharmaceutics classification (BCS) to guide oral drug product development.

Abstract: The main objective of this work was to investigate in-silico predictions of physicochemical properties, in order to guide oral drug development by provisional biopharmaceutics classification system (BCS). Four in-silico methods were used to estimate LogP: group contribution (CLogP) using two different software programs, atom contribution (ALogP), and element contribution (KLogP). The correlations (r(2)) of CLogP, ALogP and KLogP versus measured LogP data were 0.97, 0.82, and 0.71, respectively. The classification of drugs with reported intestinal permeability in humans was correct for 64.3%-72.4% of the 29 drugs on the dataset, and for 81.82%-90.91% of the 22 drugs that are passively absorbed using the different in-silico algorithms. Similar permeability classification was obtained with the various in-silico methods. The in-silico calculations, along with experimental melting points, were then incorporated into a thermodynamic equation for solubility estimations that largely matched the reference solubility values. It was revealed that the effect of melting point on the solubility is minor compared to the partition coefficient, and an average melting point (162.7 °C) could replace the experimental values, with similar results. The in-silico methods classified 20.76% (± 3.07%) as Class 1, 41.51% (± 3.32%) as Class 2, 30.49% (± 4.47%) as Class 3, and 6.27% (± 4.39%) as Class 4. In conclusion, in-silico methods can be used for BCS classification of drugs in early development, from merely their molecular formula and without foreknowledge of their chemical structure, which will allow for the improved selection, engineering, and developability of candidates. These in-silico methods could enhance success rates, reduce costs, and accelerate oral drug products development.

in-silico
biopharmaceutics classification system
intestinal permeability
solubility
partition coefficient


Co-culturing nucleus pulposus mesenchymal stem cells with notochordal cell-rich nucleus pulposus explants attenuates tumor necrosis factor-α-induced senescence.

Abstract:
BACKGROUND
Cell therapy for the treatment of intervertebral disc degeneration (IDD) faces serious barriers since tissue-specific adult cells such as nucleus pulposus cells (NPCs) have limited proliferative ability and poor regenerative potential; in addition, it is difficult for exogenous adult stem cells to survive the harsh environment of the degenerated intervertebral disc. Endogenous repair by nucleus pulposus mesenchymal stem cells (NPMSCs) has recently shown promising regenerative potential for the treatment of IDD. Notochordal cells (NCs) and NC-conditioned medium (NCCM) have been proven to possess regenerative ability for the treatment of IDD, but this approach is limited by the isolation and passaging of NCs. Our previous study demonstrated that modified notochordal cell-rich nucleus pulposus (NC-rich NP) has potential for the repair of IDD. However, whether this can protect NPMSCs during IDD has not been evaluated.

METHODS
In the current study, tumor necrosis factor (TNF)-α was used to mimic the inflammatory environment of IDD. Human NPMSCs were cocultured with NC-rich NP explants from healthy rabbit lumbar spine with or without TNF-α. Cell proliferation and senescence were analyzed to investigate the effect of NC-rich NP explants on TNF-α-treated NPMSCs. The expression of mRNA encoding proteins related to matrix macromolecules (such as aggrecan, Sox-9, collagen Iα, and collagen IIα), markers related to the nucleus pulposus cell phenotype (including CA12, FOXF1, PAX1, and HIF-1α), and senescence markers (such as p16, p21, and p53), senescence-associated proinflammatory cytokines (IL-6), and extracellular proteases (MMP-13, ADAMTS-5) was assessed. The protein expression of CA12 and collagen II was also evaluated.

RESULTS
After a 7-day treatment, the NC-rich NP explant was found to enhance cell proliferation, decrease cellular senescence, promote glycosaminoglycan (GAG), collagen II, and CA12 production, upregulate the expression of extracellular matrix (ECM)-related genes (collagen I, collagen II, SOX9, and ACAN), and enhance the expression of nucleus pulposus cell (NPC) markers (HIF-1α, FOXF1, PAX1, and CA12).

CONCLUSION
Modified NC-rich NP explants can attenuate TNF-α-induced degeneration and senescence of NPMSCs in vitro. Our findings provide new insights into the therapeutic potential of NC-rich NP for the treatment of IDD.

Li|Xiao-Chuan|XC| Wang|Mao-Sheng|MS| Liu|Wei|W| Zhong|Cheng-Fan|CF| Deng|Gui-Bin|GB| Luo|Shao-Jian|SJ| Huang|Chun-Ming|CM|

Notochordal cell-rich nucleus pulposus explants


Reconstruction of complex soft-tissue defects around the knee joint with distally based split vastus lateralis musculocutaneous flap: a new technique.

Abstract:
AIMS
The aim of this study was to report our experience of using distally based spilt vastus lateralis musculocutaneous flaps for soft-tissue defects around the knee joint - a new technique.

MATERIAL AND METHODS
Cadaver dissection studies were conducted in three cadavers to demonstrate perforators entering the lower third of the vastus lateralis muscle arising from the superior lateral genicular artery. Its application in eight clinical cases for the reconstruction of soft-tissue defects around the knee joint is reported.

RESULTS
Seven out of eight flaps survived well without any flap loss. One flap with a skin island measuring 12 × 20 cm suffered a loss of 2 cm distally. This was later treated with skin grafting. Six out of eight donor sites were closed primarily. Six patients achieved full functional range of motion by 3 months. One patient had a 10° limitation of knee extension. One patient had foot drop due to primary injury and walks with a limping gait.

CONCLUSIONS
This flap is a new reconstructive option for knee defects. It can reach distally up to the tibial tuberosity and does not require an intraoperative change of position. The donor site can be closed primarily and is hidden inside the clothing. The function of the knee is not affected as the majority of the muscle is kept in continuity.

Sahasrabudhe|P|P| Panse|N|N| Baheti|B|B| Jadhav|A|A| Joshi|N|N| Chandanwale|A|A|

D000328:Adult
D015331:Cohort Studies
D005260:Female
D005500:Follow-Up Studies
D006084:Graft Rejection
D006085:Graft Survival
D006801:Humans
D007194:India
D015601:Injury Severity Score
D007719:Knee Joint
D008297:Male
D008875:Middle Aged
D064827:Myocutaneous Flap
D052097:Quadriceps Muscle
D012189:Retrospective Studies
D018570:Risk Assessment
D012867:Skin
D017695:Soft Tissue Injuries
D013997:Time Factors
D016896:Treatment Outcome
D014945:Wound Healing

Superior lateral genicular artery perforators


IRF8 Transcription Factor Controls Survival and Function of Terminally Differentiated Conventional and Plasmacytoid Dendritic Cells, Respectively.

Abstract: Interferon regulatory factor-8 (IRF8) has been proposed to be essential for development of monocytes, plasmacytoid dendritic cells (pDCs) and type 1 conventional dendritic cells (cDC1s) and remains highly expressed in differentiated DCs. Transcription factors that are required to maintain the identity of terminally differentiated cells are designated "terminal selectors." Using BM chimeras, conditional Irf8(fl/fl) mice and various promotors to target Cre recombinase to different stages of monocyte and DC development, we have identified IRF8 as a terminal selector of the cDC1 lineage controlling survival. In monocytes, IRF8 was necessary during early but not late development. Complete or late deletion of IRF8 had no effect on pDC development or survival but altered their phenotype and gene-expression profile leading to increased T cell stimulatory function but decreased type 1 interferon production. Thus, IRF8 differentially controls the survival and function of terminally differentiated monocytes, cDC1s, and pDCs.

Sichien|Dorine|D|
Scott|Charlotte L|CL|
Martens|Liesbet|L|
Vanderkerken|Matthias|M|
Van Gassen|Sofie|S|
Plantinga|Maud|M|
Joeris|Thorsten|T|
De Prijck|Sofie|S|
Vanhoutte|Leen|L|
Vanheerswynghels|Manon|M|
Van Isterdael|Gert|G|
Toussaint|Wendy|W|
Madeira|Filipe Branco|FB|
Vergote|Karl|K|
Agace|William W|WW|
Clausen|Björn E|BE|
Hammad|Hamida|H|
Dalod|Marc|M|
Saeys|Yvan|Y|
Lambrecht|Bart N|BN|
Guilliams|Martin|M|

IRF8
transcription factor
plasmacytoid dendritic cell
dendritic cell
development
monocyte
terminal selector
lineage
IRF4


A novel family of plant nuclear envelope-associated proteins.

Abstract: This paper describes the characterisation of a new family of higher plant nuclear envelope-associated proteins (NEAPs) that interact with other proteins of the nuclear envelope. In the model plant Arabidopsis thaliana, the family consists of three genes expressed ubiquitously (AtNEAP1-3) and a pseudogene (AtNEAP4). NEAPs consist of extensive coiled-coil domains, followed by a nuclear localisation signal and a C-terminal predicted transmembrane domain. Domain deletion mutants confirm the presence of a functional nuclear localisation signal and transmembrane domain. AtNEAP proteins localise to the nuclear periphery as part of stable protein complexes, are able to form homo- and heteromers, and interact with the SUN domain proteins AtSUN1 and AtSUN2, involved in the linker of nucleoskeleton and cytoskeleton (LINC) complex. An A. thaliana cDNA library screen identified a putative transcription factor called AtbZIP18 as a novel interactor of AtNEAP1, which suggest a connection between NEAP and chromatin. An Atneap1 Atneap3 double-knockout mutant showed reduced root growth, and altered nuclear morphology and chromatin structure. Thus AtNEAPs are suggested as inner nuclear membrane-anchored coiled-coil proteins with roles in maintaining nuclear morphology and chromatin structure.

Pawar|Vidya|V|
Poulet|Axel|A|
Détourné|Gwénaëlle|G|
Tatout|Christophe|C|
Vanrobays|Emmanuel|E|
Evans|David E|DE|
Graumann|Katja|K|

D017360:Arabidopsis
D029681:Arabidopsis Proteins
D015153:Blotting, Western
D002843:Chromatin
D003001:Cloning, Molecular
D003599:Cytoskeleton
D017343:Genes, Plant
D008565:Membrane Proteins
D018613:Microscopy, Confocal
D009685:Nuclear Envelope
D010802:Phylogeny
D020798:Two-Hybrid System Techniques

higher plant
nuclear envelope
Arabidopsis thaliana
nucleoskeleton
chromatin
LINC complex
inner nuclear membrane
nuclear lamina
nucleus.


Patterns of tau pathology identified with 18 F-MK-6240 PET imaging.

Abstract:
INTRODUCTION
Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer's disease (AD) pathology. We evaluated the suitability of 18 F-MK-6240 in a clinical sample and determined the relationships among 18 F-MK-6240 binding, age, cognition, and cerebrospinal fluid (CSF)-based AD biomarkers.

METHODS
Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty-one participants had lumbar puncture for CSF measurement of amyloid beta (Aβ)42 , tau, and phosphorylated tau (p-tau).

RESULTS
18 F-MK-6240 recapitulated Braak staging and correlated with CSF tau and p-tau, normalized to Aβ42 . 18 F-MK-6240 negatively correlated with age across Braak regions in amyloid-positive participants, consistent with greater tau pathology in earlier onset AD. Domain-specific, regional patterns of 18 F-MK-6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid-positive participants.

DISCUSSION
18 F-MK-6240 can approximate Braak staging across the AD continuum and provide region-dependent insights into biomarker-based AD models.

Kreisl|William Charles|WC|
Lao|Patrick J|PJ|
Johnson|Aubrey|A|
Tomljanovic|Zeljko|Z|
Klein|Julia|J|
Polly|Krista|K|
Maas|Benjamin|B|
Laing|Krystal K|KK|
Chesebro|Anthony G|AG|
Igwe|Kay|K|
Razlighi|Qolamreza R|QR|
Honig|Lawrence S|LS|
Yan|Xinyu|X|
Lee|Seonjoo|S|
Mintz|Akiva|A|
Luchsinger|José A|JA|
Stern|Yaakov|Y|
Devanand|D P|DP|
Brickman|Adam M|AM|

Alzheimer's disease
cognition
cerebrospinal fluid
MK-6240
amyloid positivity
tau positivity
tau positron emission tomography


The Use of Telehealth in School-Based Health Centers.

Abstract: Telehealth is a growing model of delivering health care. School-based health centers (SBHCs) provide access to health care for youth in schools and increasingly use telehealth in care delivery. This article examines the recent growth of telehealth use in SBHCs, and characteristics of SBHCs using telehealth, including provider types, operational characteristics, and schools and students served. The percentage of SBHCs using telehealth grew from 7% in 2007-2008 to 19% in 2016-2017. Over 1 million students in over 1800 public schools have access to an SBHC using telehealth, which represents 2% of students and nearly 2% of public schools in the United States. These SBHCs are primarily in rural communities and sponsored by hospitals. This growing model presents an opportunity to expand health care access to youth, particularly in underserved areas in the United States and globally. Further research is needed to fully describe how telehealth programs are implemented in school settings and their potential impacts.

telehealth
school-based health centers
adolescents
rural health
underserved populations


Expression of interleukin-6 in ocular surface squamous neoplasia.

Abstract:
Purpose
Interleukin-6 (IL-6) is an important cytokine in the cascade of inflammation and cancer progression. The aim of this study was to identify IL-6 expression in ocular surface squamous neoplasia (OSSN) in comparison with non-neoplastic conjunctival tissue.

Methods
Twenty paraffin-embedded tissue sections of conjunctiva from patients with OSSN including conjunctival intraepithelial neoplasia (CIN) in all grades of severity and squamous cell carcinoma (SCC) were assessed by immunohistochemistry staining for IL-6. Twenty non-neoplastic conjunctival sections from age matched patients were selected as the control group. Tissues with more than one focus of inflammatory cell infiltration were excluded from the study. The mean area of positive staining was recorded and the intensity of staining was scored in both groups and compared by statistical methods.

Results
The mean staining area in the dysplasia group was significantly more than non-neoplastic conjunctival tissue (63.5±25.96 and 30±15.98 percent respectively; P-value of <0.0001). Nuclear staining was observed in both groups and the difference was not statistically significant.

Conclusion
IL-6 expressed more in the dysplastic group in compare to non-neoplastic conjunctiva and can therefore be used to diagnose dysplastic state of the conjunctiva; however, in our study, intensity of staining does not correlate with the severity of dysplasia statistically; most probably because of a low sample size in each category. The role of nuclear staining is not clear. Our findings can be an introduction toward targeted treatment of ocular surface neoplasia by the aim of newer anti-IL agents. Further investigation is needed.

interleukin-6
conjunctival intraepithelial neoplasia
squamous cell carcinoma
dysplasia


Treadmill gait training combined with functional electrical stimulation on hip abductor and ankle dorsiflexor muscles for chronic hemiparesis.

Abstract: The purpose of this study was to investigate the effects of treadmill training (TT) with functional electrical stimulation (FES) applied to the gluteus medius (GM) and tibialis anterior (TA) muscles on gait and balance performance in individuals with chronic hemiparetic stroke. Thirty-six participants with chronic hemiparesis were recruited to this study and randomly distributed into three groups: TT with FES applied to the GM and TA muscles (TTFES-GM+TA group, 12 patients); TT with FES applied to the TA muscle (TTFES-TA group, 12 patients); and TT only (control group, 12 patients). All participants underwent 20 sessions of TT with a harness (30min five times per week for 4 weeks). They also received regular physical therapy for 1h five times per week for 4 weeks. All participants were assessed before and after training using digital muscle testing, the Medical Research Council (MRC) scale, the 6-min walk test (6MWT), and spatiotemporal parameters. After training, the TTFES-GM+TA group showed significant improvement in hip abductor strength, Berg Balance Scale score, 6MWT result, MRC scale score grade, gait velocity, and cadence compared to the TTFES-TA group and control group. These findings show that TT with FES applied to the GM and TA muscles increased lower limb muscle strength and improved balance and gait capacities. Therefore, TT with FES applied to the GM and TA could be a beneficial intervention in clinical settings for individuals with chronic hemiparetic stroke.

Cho|Min-Kwon|MK| Kim|Jung-Hyun|JH| Chung|Yijung|Y| Hwang|Sujin|S|

Gait
Functional electrical stimulation
Treadmill training
Stroke


Association of treatments for acute myocardial infarction and survival for seven common comorbidity states: a nationwide cohort study.

Abstract:
BACKGROUND
Comorbidity is common and has a substantial negative impact on the prognosis of patients with acute myocardial infarction (AMI). Whilst receipt of guideline-indicated treatment for AMI is associated with improved prognosis, the extent to which comorbidities influence treatment provision its efficacy is unknown. Therefore, we investigated the association between treatment provision for AMI and survival for seven common comorbidities.

METHODS
We used data of 693,388 AMI patients recorded in the Myocardial Ischaemia National Audit Project (MINAP), 2003-2013. We investigated the association between comorbidities and receipt of optimal care for AMI (receipt of all eligible guideline-indicated treatments), and the effect of receipt of optimal care for comorbid AMI patients on long-term survival using flexible parametric survival models.

RESULTS
A total of 412,809 [59.5%] patients with AMI had at least one comorbidity, including hypertension (302,388 [48.7%]), diabetes (122,228 [19.4%]), chronic obstructive pulmonary disease (COPD, 89,221 [14.9%]), cerebrovascular disease (51,883 [8.6%]), chronic heart failure (33,813 [5.6%]), chronic renal failure (31,029 [5.0%]) and peripheral vascular disease (27,627 [4.6%]). Receipt of optimal care was associated with greatest survival benefit for patients without comorbidities (HR 0.53, 95% CI 0.51-0.56) followed by patients with hypertension (HR 0.60, 95% CI 0.58-0.62), diabetes (HR 0.83, 95% CI 0.80-0.87), peripheral vascular disease (HR 0.85, 95% CI 0.79-0.91), renal failure (HR 0.89, 95% CI 0.84-0.94) and COPD (HR 0.90, 95% CI 0.87-0.94). For patients with heart failure and cerebrovascular disease, optimal care for AMI was not associated with improved survival.

CONCLUSIONS
Overall, guideline-indicated care was associated with improved long-term survival. However, this was not the case in AMI patients with concomitant heart failure or cerebrovascular disease. There is therefore a need for novel treatments to improve outcomes for AMI patients with pre-existing heart failure or cerebrovascular disease.

Acute myocardial infarction
Survival
Comorbidity
Guideline care


Using cavity microelectrodes for electrochemical noise studies of oxygen-evolving catalysts.

Abstract: Cavity microelectrodes were used as a binder-free platform to evaluate oxygen evolution reaction (OER) electrocatalysts with respect to gas bubble formation and departure. Electrochemical noise measurements were performed by using RuO2 as a benchmark catalyst and the perovskite La0.58 Sr0.4 Fe0.8 Co0.2 O3 as a non-noble metal OER catalyst with lower intrinsic conductivity. Changes in the current during the OER originate from variations in electrolyte resistance during the formation of the gas phase and partial coverage of the active area. Fluctuations observed in current and conductance transients were used to establish the contribution from the ohmic overpotential and to determine the characteristic frequency of oxygen evolution. The proposed quantitative determination of gas bubble growth and departure opens up the route for a rational interface design by considering gas bubble growth and departure as a main contributing factor to the overall electrocatalytic activity at high current densities.

Rincón|Rosalba A|RA|
Battistel|Alberto|A|
Ventosa|Edgar|E|
Chen|Xingxing|X|
Nebel|Michaela|M|
Schuhmann|Wolfgang|W|

cavity microelectrodes
oxygen
electrochemistry
gas-evolving electrodes
perovskite phases


Two Distinct Neural Timescales for Predictive Speech Processing.

Abstract: During speech listening, the brain could use contextual predictions to optimize sensory sampling and processing. We asked if such predictive processing is organized dynamically into separate oscillatory timescales. We trained a neural network that uses context to predict speech at the phoneme level. Using this model, we estimated contextual uncertainty and surprise of natural speech as factors to explain neurophysiological activity in human listeners. We show, first, that speech-related activity is hierarchically organized into two timescales: fast responses (theta: 4-10 Hz), restricted to early auditory regions, and slow responses (delta: 0.5-4 Hz), dominating in downstream auditory regions. Neural activity in these bands is selectively modulated by predictions: the gain of early theta responses varies according to the contextual uncertainty of speech, while later delta responses are selective to surprising speech inputs. We conclude that theta sensory sampling is tuned to maximize expected information gain, while delta encodes only non-redundant information. VIDEO ABSTRACT.

speech processing
neural networks
uncertainty
surprise
MEG
auditory processing
delta oscillations
predictive coding
temporal response functions
theta oscillations


Reslizumab in patients with inadequately controlled late-onset asthma and elevated blood eosinophils.

Abstract:
INTRODUCTION
Asthma with adult onset and elevated blood eosinophils is a difficult-to-treat subgroup. This post hoc analysis evaluated reslizumab, an anti-interleukin-5 monoclonal antibody, in patients with late-onset eosinophilic asthma.

METHODS
Data from two 52-week placebo-controlled trials of reslizumab IV 3 mg/kg every 4 weeks in patients aged 12-75 years with inadequately controlled asthma, ≥1 asthma exacerbation within 12 months, and screening blood eosinophils ≥400/μL (NCT01287039/NCT01285323) were stratified by age of asthma onset (<40 or ≥40 years). Annual clinical asthma exacerbation rates, change in lung function, and patient-reported outcomes were analyzed.

RESULTS
273 patients with late-onset asthma (placebo, n = 130; reslizumab, n = 143) and 658 with early-onset asthma (placebo, n = 336; reslizumab, n = 322) were included. Baseline demographics were similar between groups. The interaction between age at onset of asthma and effect of reslizumab on asthma exacerbations was statistically significant (p = 0.0083). Compared with placebo, reslizumab produced a 75% relative reduction in asthma exacerbations in patients with late-onset asthma (rate ratio [RR] 0.25; 95% confidence interval [CI], 0.16, 0.40), substantially larger than the reduction in earlier onset patients (RR 0.58; 95% CI, 0.44, 0.76). Similar findings were observed for other measures of asthma, including forced expiratory volume in 1 s (FEV1). The adverse event profile of reslizumab was similar in patients with early- or late-onset asthma.

CONCLUSIONS
Compared with placebo, reslizumab produced larger reductions in asthma exacerbations and larger improvements in lung function in patients with late versus early-onset asthma.

Brusselle|Guy|G| Germinaro|Matthew|M| Weiss|Sivan|S| Zangrilli|James|J|

D016032:Randomized Controlled Trials as Topic


The Continuing and Growing Epidemic of Chronic Low Back Pain.

Abstract: Because of the great prevalence of chronic pain, it is not surprising that there have been a number of influential reports by the Institute of Medicine, National Institutes of Health, and the World Health Organization that have documented the medical, social and economic problems caused by it, and the need for better pain-management programs. The present article briefly reviews these reports, and then focuses on three important areas that need to be considered when addressing the continuing and growing epidemic of one of the most prevalent types of chronic pain [chronic low back pain (CLBP)]: the biopsychosocial model of chronic pain; the paradigm shift in medicine from a disease model to an illness model of CLBP; and a review of the treatment- and cost-effectiveness of interdisciplinary chronic pain management programs. This overview will serve as an important prelude to other topics related to low back pain included in this Special Issue of Healthcare. Topics covered will range from assessment and treatment approaches, to important psychosocial mediators/moderators such as coping and pain beliefs.


Genotypic and phenotypic profiles of antibiotic-resistant bacteria isolated from hospitalised patients in Bangladesh.

Abstract:
OBJECTIVES
Characterisation of resistance phenotype and genotype is crucial to understanding the burden and transmission of antimicrobial resistance (AMR). This study aims to determine the spectrum of AMR and associated genes encoding aminoglycoside, macrolide and β-lactam classes of antimicrobials in bacteria isolated from hospitalised patients in Bangladesh.

METHODS
430 bacterial isolates from patients with respiratory, intestinal, wound infections and typhoid fever, presenting to clinical care from 2015 to 2019, were examined. They included Escherichia coli (n = 85); Staphylococcus aureus (n = 84); Salmonella typhi (n = 82); Klebsiella pneumoniae (n = 42); Streptococcus pneumoniae (n = 36); coagulase-negative staphylococci (n = 28); Enterococcus faecalis (n = 27); Pseudomonas aeruginosa (n = 26); and Acinetobacter baumannii (n = 20). Reconfirmation of these clinical isolates and antimicrobial susceptibility tests was performed. PCR amplification using resistance gene-specific primers was done, and the amplified products were confirmed by Sanger sequencing.

RESULTS
53% of isolates were multidrug-resistant (MDR), including 97% of Escherichia coli. There was a year-wise gradual increase in MDR isolates from 2015 to 2018, and there was an almost twofold increase in the number of MDR strains isolated in 2019 (P = 0.00058). Among the 5 extended-spectrum β-lactamases investigated, CTX-M-1 was the most prevalent (63%) followed by NDM-1 (22%); Escherichia coli was the major reservoir of these genes. The ermB (55%) and aac(6')-Ib (35%) genes were the most frequently detected macrolide and aminoglycoside resistance genes, respectively.

CONCLUSION
MDR pathogens are highly prevalent in hospital settings of Bangladesh.

Sarjana Safain|Kazi|K|
Bhuyan|Golam Sarower|GS|
Hassan Hasib|Saad|S|
Islam|Mohammad Sazzadul|MS|
Mahmud-Un-Nabi|Mohammad Al|MA|
Sultana|Rosy|R|
Tasnim|Sadia|S|
Noor|Farjana Akther|FA|
Sarker|Suprovath Kumar|SK|
Islam|Md Tarikul|MT|
Rahat|Asifuzzaman|A|
Leung|Daniel T|DT|
Domman|Daryl|D|
Manzoor|Farhana|F|
Anwar|Sajid|S|
Majid Bhuiyan|Md Abdul|MA|
Chowdhury|Emran Kabir|EK|
Qadri|Syed Saleheen|SS|
Qadri|Firdausi|F|
Mannoor|Kaiissar|K|

D024901:Drug Resistance, Multiple, Bacterial

antimicrobial resistance
aminoglycoside
macrolide
wound infections
typhoid fever
extended-spectrum β-lactamase
acute respiratory infections
diarrhoea
multidrug resistance


Using models to establish the financially optimum strategy for Irish dairy farms.

Abstract: Determining the effect of a change in management on farm with differing characteristics is a significant challenge in the evaluation of dairy systems due to the interacting components of complex biological systems. In Ireland, milk production is increasing substantially following the abolition of the European Union milk quota regime in 2015. There are 2 main ways to increase the milk production on farm (within a fixed land base): either increase the number of animals (thus increasing the stocking rate) or increase the milk production per animal through increased feeding or increased lactation length. In this study, the effect of increased concentrate feeding or an increase in grazing intensity was simulated to determine the effect on the farm system and its economic performance. Four stocking rates (2.3, 2.6, 2.9, and 3.2 cow/ha) and 5 different concentrate supplementation strategies (0, 180, 360, 600, and 900 kg of dry matter/lactation) resulting in 20 different scenarios were evaluated across different milk, concentrate, and silage purchase prices. Each simulation was run across 10 yr of meteorological data, which had been recorded over the period 2004 to 2013. Three models-the Moorepark and St Gilles grass growth model, the pasture-based herd dynamic milk model, and the Moorepark dairy systems model-were integrated and applied to simulate the different scenarios. Overall, this study has demonstrated that the most profitable scenario was a stocking rate of 2.6 cow/ha with a concentrate supplementation of 600 kg of dry matter/cow. The factor that had the greatest influence on profitability was variability of milk price.

Ruelle|E|E| Delaby|L|L| Wallace|M|M| Shalloo|L|L|

models
grazing intensity
economic
concentrate supplementation


Four days of simulated shift work reduces insulin sensitivity in humans.

Abstract:
AIM
The aim of this study was to investigate the effects of 4 consecutive simulated night shifts on glucose homeostasis, mitochondrial function and central and peripheral rhythmicities compared with a simulated day shift schedule.

METHODS
Seventeen healthy adults (8M:9F) matched for sleep, physical activity and dietary/fat intake participated in this study (night shift work n = 9; day shift work n = 8). Glucose tolerance and insulin sensitivity before and after 4 nights of shift work were measured by an intravenous glucose tolerance test and a hyperinsulinaemic euglycaemic clamp respectively. Muscles biopsies were obtained to determine insulin signalling and mitochondrial function. Central and peripheral rhythmicities were assessed by measuring salivary melatonin and expression of circadian genes from hair samples respectively.

RESULTS
Fasting plasma glucose increased (4.4 ± 0.1 vs. 4.6 ± 0.1 mmol L-1 ; P = .001) and insulin sensitivity decreased (25 ± 7%, P < .05) following the night shift, with no changes following the day shift. Night shift work had no effect on skeletal muscle protein expression (PGC1α, UCP3, TFAM and mitochondria Complex II-V) or insulin-stimulated pAkt Ser473, pTBC1D4Ser318 and pTBC1D4Thr642. Importantly, the metabolic changes after simulated night shifts occurred despite no changes in the timing of melatonin rhythmicity or hair follicle cell clock gene expression across the wake period (Per3, Per1, Nr1d1 and Nr1d2).

CONCLUSION
Only 4 days of simulated night shift work in healthy adults is sufficient to reduce insulin sensitivity which would be expected to increase the risk of T2D.

Bescos|R|R|
Boden|M J|MJ|
Jackson|M L|ML|
Trewin|A J|AJ|
Marin|E C|EC|
Levinger|I|I|
Garnham|A|A|
Hiam|D S|DS|
Falcao-Tebas|F|F|
Conte|F|F|
Owens|J A|JA|
Kennaway|D J|DJ|
McConell|G K|GK|

D010561:Personnel Staffing and Scheduling

shift work
insulin
glucose
melatonin
mitochondria
circadian rhythm


Outdoor air pollution in India is not only an urban problem.

Abstract: Urban outdoor air pollution in the developing world, mostly due to particulate matter with diameters smaller than 2.5 µm (PM2.5), has been highlighted in recent years. It leads to millions of premature deaths. Outdoor air pollution has also been viewed mostly as an urban problem. We use satellite-derived demarcations to parse India's population into urban and nonurban regions, which agrees with the census data. We also use the satellite-derived surface PM2.5 levels to calculate the health impacts in the urban and nonurban regions. We show that outdoor air pollution is just as severe in nonurban regions as in the urban regions of India, with implications to monitoring, regulations, health, and policy.

air pollution
India
PM2.5
health impacts


Serum resistin is associated with impaired endothelial function and a higher rate of adverse cardiac events in patients with peripheral artery disease.

Abstract:
OBJECTIVE
Resistin is a hormone that has been associated with metabolic syndrome and cardiovascular disease. The role of resistin in patients with peripheral artery disease (PAD) has not been fully explored. This study seeks to understand the relationship between serum resistin, vascular function, and cardiovascular outcomes in patients with PAD.

METHODS
There were 106 patients with PAD who were recruited between 2011 and 2016. Patients attended a baseline visit during which a comprehensive vascular physiology assessment including medical and surgical history, radial artery tonometry, and flow mediated-vasodilation (FMD) was completed. A blood sample was drawn, and serum resistin was assayed using enzyme-linked immunosorbent assay kits. Using the time of study enrollment as the time of origin, incident major adverse cardiac events (MACEs) were identified by subsequent chart review and defined as a composite end point of myocardial infarction, coronary revascularization, transient ischemic attack, stroke, or death from a cardiac cause.

RESULTS
Patients had a mean age of 68 ± 8 years, were largely white (75%), and had comorbidities commonly associated with PAD including hypertension (92%), hyperlipidemia (87%), coronary artery disease (37%), and diabetes mellitus (38%). After stratification by resistin quartile, higher resistin quartiles were significantly associated with an older age, a greater number of pack-years smoked, and a lower estimated glomerular filtration rate. Despite similar comorbidities and medication use, endothelial function, as measured by FMD, was significantly lower with increasing resistin quartile (I, 9.1% ± 3.3%; II, 7.1% ± 3.5%; III, 5.8% ± 4.0%; IV, 5.6% ± 3.5%; P = .002). In multivariable linear regression, higher resistin quartiles (III and IV) were associated with lower FMD relative to quartile I after adjusting for several patient characteristics, medications, and comorbidities (III, -2.26 [95% confidence interval (CI), -4.51 to -0.01; P = .05]; IV, -2.53 [95% CI, -4.87 to -0.20; P = .03]). During a median follow-up period of 36 months (interquartile range, 29-45 months), 21 patients experienced the primary end point. In a Cox proportional hazards model adjusted for smoking status, coronary artery disease, and age, each 1 ng/mL increase in resistin was associated with a 10% increased risk of MACEs (hazard ratio, 1.10; 95% CI, 1.00-1.20; P = .04).

CONCLUSIONS
In patients with PAD, higher levels of resistin were associated with impaired endothelial function and an increased rate of MACEs. These results suggest that resistin may be a marker or effector of impaired vascular physiology and adverse cardiac outcomes in patients with PAD. Further research is needed to determine the potential mechanisms by which resistin may impair endothelial function and increase MACEs in this population.

Ramirez|Joel L|JL|
Khetani|Sukaynah A|SA|
Zahner|Greg J|GJ|
Spaulding|Kimberly A|KA|
Schaller|Melinda S|MS|
Gasper|Warren J|WJ|
Hills|Nancy K|NK|
Schafer|Anne L|AL|
Grenon|S Marlene|SM|

Resistin
Endothelial function
Peripheral artery disease
Adipokines
Flow-mediated vasodilation


Effects of methylmercury and retinol palmitate co-administration in rats during pregnancy and breastfeeding: Metabolic and redox parameters in dams and their offspring.

Abstract: Ubiquitous low-dose methylmercury (MeHg) exposure through an increased fish consumption represents a global public health problem, especially among pregnant women. A plethora of micronutrients presented in fish affects MeHg uptake/distribution, but limited data is available. Vitamin A (VitA), another fish micronutrient is used in nutritional supplementation, especially during pregnancy. However, there is no information about the health effects arising from their combined exposure. Therefore, the present study aimed to examine the effects of both MeHg and retinyl palmitate administered on pregnant and lactating rats in metabolic and redox parameters from dams and their offspring. Thirty Wistar female rats were orally supplemented with MeHg (0,5 mg/kg/day) and retinyl palmitate (7500 µg RAE/kg/day) via gavage, either individually or in combination from the gestational day 0 to weaning. For dams (150 days old) and their offspring (31 days old), glycogen accumulation (hepatic and cardiac) and retinoid contents (plasma and liver) were analyzed. Hg deposition in liver tissue was quantified. Redox parameters (liver, kidney, and heart) were evaluated for both animals. Cytogenetic damage was analyzed with micronucleus test. Our results showed no general toxic or metabolic alterations in dams and their offspring by MeHg-VitA co-administration during pregnancy and lactation. However, increased lipoperoxidation in maternal liver and a disrupted pro-oxidant response in the heart of male pups was encountered, with apparently no particular effects in the antioxidant response in female offspring. GST activity in dam kidney was altered leading to possible redox disruption of this tissue with no alterations in offspring. Finally, the genomic damage was exacerbated in both male and female pups. In conclusion, low-dose MeHg exposure and retinyl palmitate supplementation during gestation and lactation produced a potentiated pro-oxidant effect, which was tissue-specific. Although this is a pre-clinical approach, we recommend precaution for pregnant women regarding food consumption, and we encourage more epidemiological studies to assess possible modulations effects of MeHg-VitA co-administration at safe or inadvertently used doses in humans, which may be related to specific pathologies in mothers and their children.

Espitia-Pérez|Pedro|P|
Albino|Suelen Marin|SM|
da Rosa|Helen Tais|HT|
Silveira|Alexandre Kleber|AK|
Espitia-Pérez|Lyda|L|
Brango|Hugo|H|
Moraes|Diogo Pompéu|DP|
Hermann|Paolla Rissi Silva|PRS|
Mingori|Moara|M|
Barreto|Fabiano|F|
Kunzler|Alice|A|
Gelain|Daniel Pens|DP|
Schnorr|Carlos Eduardo|CE|
Moreira|José Cláudio Fonseca|JCF|

D011297:Prenatal Exposure Delayed Effects

Methylmercury
Pregnancy
Vitamin A
Co-exposure
Oxidative stress


Unexpected Intraoperative Findings, Situations, and Complications in Bariatric Surgery.

Abstract:
BACKGROUND
Bariatric surgery is considered a safe therapy to treat obesity. Postoperative complications are well known; however, there is a lack of data describing intraoperative complications and/or unexpected findings, and if there is further impact on outcomes.

METHODS
Retrospective study with patients operated between 2013 and 2016 at a single institution. All operative information was collected prospectively and aimed to analyze the incidence and causes of unexpected intraoperative findings, complications, change in surgical plan, extra surgeries, and procedure interruption in patients submitted to bariatric surgery. Secondarily, a morbidity analysis was performed, correlating intraoperative complications with postoperative complications and length of stay.

RESULTS
Four-hundred and five patients were included. Female sex comprised 82% of cases, and a median age of 38 years old was observed; almost 90% were gastric bypass. In 29.3% of cases, there were intraoperative findings, mainly adhesions, abdominal wall hernias, positive methylene blue test, hiatal hernias, and gastrointestinal stromal tumors. Associated surgeries were performed in 8.6% cases, and intraoperative adverse events reported in 7.1%, where organ injury and anastomosis problems were the most frequent. A change in the operative plan was done in 0.9% and surgery interruption in 1.2% of the cases. Early complications were observed in 6.6%. There was no correlation between intraoperative complications and length of stay or early complications.

CONCLUSION
Unexpected intraoperative findings/complications are common in bariatric surgery, but without increasing morbidity or length of stay. Surgery suspension, change in the planned technique, or adding extra (non-bariatric) procedures may occur.

Joo|Paul|P|
Guilbert|Lizbeth|L|
Sepúlveda|Elisa M|EM|
Ortíz|Cristian J|CJ|
Donatini|Gianluca|G|
Zerrweck|Carlos|C|0000-0001-7358-2652

Obesity
Postoperative complications
Intraoperative complications
Unexpected findings
Intraoperative adverse events
Bariatric surgery complications
Laparoscopic gastric bypass
Laparoscopic sleeve gastrectomy
Morbid obesity


Gastrocnemius fascicle and achilles tendon length at the end of the eccentric phase in a single and multiple countermovement hop.

Abstract: The purpose of this investigation was to compare fascicle and tendon length of the gastrocnemius at the end of the eccentric phase during a hop utilizing a single countermovement (sCM) versus multiple countermovement (mCM1, mCM2, mCM3) strategy. Seventeen healthy males performed nine hopping trials of sCM and nine trials of mCM. Ankle and knee joint angle and lower leg length from videography and muscle ultrasound were used to calculate muscle-tendon unit (MTU), fascicle and tendon length. Sacral marker data was used to determine hopping height. Force- and displacement-time curves were utilized to calculate work. Muscle activity of the lateral and medial gastrocnemius was also measured. Fascicle length was significantly shorter (mCM3: 6.2 ± 1.5 cm, sCM: 7.3 ± 2.0 cm) and tendon length was significantly longer (mCM3: 36.5 ± 3.6 cm, sCM: 35.5 ± 3.8 cm) at the end of the eccentric phase in mCM3 in comparison to sCM. Maximal hopping height (mCM: 14.6 ± 3.1 cm, sCM: 13.1 ± 2.5 cm), eccentric phase gastrocnemius muscle activity (mCM medial gastrocnemius: 0.10 ± 0.03 mV, mCM lateral gastrocnemius: 0.08 ± 0.04 mV, sCM medial gastrocnemius: 0.07 ± 0.03 mV, sCM lateral gastrocnemius: 0.05 ± 0.04 mV), and both eccentric (mCM3: 46.6 ± 19.4 J, sCM: 38.5 ± 15.9 J) and concentric work (mCM3: 87.6 ± 26.5 J, sCM: 80.9 ± 27.6 J) were significantly higher for mCM3 compared to sCM. The results indicate that a multiple countermovement hop strategy results in shorter fascicle length and longer tendon length at the end of the eccentric phase. In addition, greater eccentric phase muscle activity during the third countermovement (mCM3) in comparison to a single countermovement hop (sCM) was observed. A multiple countermovement strategy appears to result in higher hopping height and greater work done in both the eccentric and concentric phase indicating possible contribution of stored-elastic energy from the tendon.

Lidstone|Daniel E|DE|
van Werkhoven|Herman|H|
Needle|Alan R|AR|
Rice|Paige E|PE|
McBride|Jeffrey M|JM|

Gastrocnemius
Performance
Ankle
Muscle activity
Jumping
Stretch-shortening cycle


The binding characteristics of isoniazid with copper-zinc superoxide dismutase and its effect on enzymatic activity.

Abstract:
BACKGROUND
Isoniazid (INH) is front-line anti-tuberculosis (TB) drugs, which are usually prescribed to TB patients for a total period of 6 months. Antituberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse reaction of TB treatment. It is reported that INH-induced hepatotoxicity is associated with oxidative stress. Superoxide dismutase (SOD, EC 1.15.1.1) is the key enzyme for the protection of oxidative stress, which catalyzes the removal of superoxide radical anion, thereby raising the need to better understand the interaction between INH and SOD.

RESULTS
The experimental results showed that the fluorescence intensity of Cu/Zn-SOD regularly decreased owing to form a 1:1 INH-SOD complex. According to the corresponding association constants (K SV) between INH and SOD obtained from Stern-Volmer plot, it is shown that values of K A are 1.01 × 10(4), 5.31 × 10(3), 3.33 × 10(3), 2.20 × 10(3) L · mol(-1) at four different temperatures, respectively. The binding constants, binding sites and the corresponding thermodynamic parameters ((Δ) H, (Δ) G and (Δ) S) were calculated. A value of 3.93 nm for the average distance between INH and chromophore of Cu/Zn-SOD was derived from Förster theory of non-radiation energy transfer. The conformational investigation showed that the presence of INH resulted in the microenvironment and conformational changes of Cu/Zn-SOD. In addition, Effects of INH on superoxide dismutase activity was examined.

CONCLUSIONS
The results show that the hydrogen bonding and van der Waals forces play major roles in stabilizing the 1:1 INH-SOD complex. After addition of INH during the range of the experiment, the conformation and microenvironment of Cu/Zn-SOD are changed, but the activity of Cu/Zn-SOD is not changed.

Du|Nana|N| Sheng|Liangquan|L| Liu|Zhaodi|Z| Hu|Xiaojuan|X| Xu|Huajie|H| Chen|Shuisheng|S|

Isoniazid
Superoxide dismutase
Interaction
Antioxidation


Uterus-preserving laparoscopic lateral suspension with mesh for pelvic organ prolapse: a patient-centred outcome report and video of a continuous series of 245 patients.

Abstract:
INTRODUCTION AND HYPOTHESIS
Changes in the psychological value of reproductive organs have led to a growing interest in uterine-preserving surgery for pelvic organ prolapse (POP). Sacral hysteropexy is considered as gold standard, although dissection of the promontory may be challenging. We show a video and present a report on a series of patients operated by laparoscopic lateral suspension with mesh as an alternative.

METHODS
Clinical evaluation was performed using the simplified Pelvic Organ Prolapse Quantification System (POP-Q). Primary outcomes were subjective and objective cure; secondary outcomes were rates for reoperation and complications. We assessed patient's satisfaction in a telephone interview using a visual analogue scale and the Patient Global Impression of Improvement Scale (PGI-I) scale.

RESULTS
Two hundred and fifty-four patients were treated between 2004 and 2011 with a median follow-up of 7.5 years. At 1 year 82.7 % of patients were asymptomatic, and anatomic success rates were 88.2 % for the anterior, 86.1 % for the apical and 80.8 % for the posterior compartment; 1.2 % had mesh exposure, and the reoperation rate was 7.4 %. More than 80 % of patients were highly satisfied with the outcome.

CONCLUSIONS
Uterine-preserving laparoscopic lateral suspension with mesh is a safe technique with promising results and low complication rates. It may be an alternative to sacral hysteropexy for high-morbidity patients.

Veit-Rubin|Nikolaus|N| Dubuisson|Jean-Bernard|JB| Lange|Sören|S| Eperon|Isabelle|I| Dubuisson|Jean|J|

Laparoscopic lateral suspension
Pelvic organ prolapse
Patient satisfaction


In Vitro Consequences of Electronic-Cigarette Flavoring Exposure on the Immature Lung.

Abstract: Background: The developing lung is uniquely susceptible and may be at increased risk of injury with exposure to e-cigarette constituents. We hypothesize that cellular toxicity and airway and vascular responses with exposure to flavored refill solutions may be altered in the immature lung. Methods: Fetal, neonatal, and adult ovine pulmonary artery smooth muscle cells (PASMC) were exposed to popular flavored nicotine-free e-cigarette refill solutions (menthol, strawberry, tobacco, and vanilla) and unflavored solvents: propylene glycol (PG) or vegetable glycerin (VG). Viability was assessed by lactate dehydrogenase assay. Brochodilation and vasoreactivity were determined on isolated ovine bronchial rings (BR) and pulmonary arteries (PA). Results: Neither PG or VG impacted viability of immature or adult cells; however, exposure to menthol and strawberry flavored solutions increased cell death. Neonatal cells were uniquely susceptible to menthol flavoring-induced toxicity, and all four flavorings demonstrated lower lethal doses (LD50) in immature PASMC. Exposure to flavored solutions induced bronchodilation of neonatal BR, while only menthol induced airway relaxation in adults. In contrast, PG/VG and flavored solutions did not impact vasoreactivity with the exception of menthol-induced relaxation of adult PAs. Conclusion: The immature lung is uniquely susceptible to cellular toxicity and altered airway responses with exposure to common flavored e-cigarette solutions.

Berkelhamer|Sara K|SK|
Helman|Justin M|JM|
Gugino|Sylvia F|SF|
Leigh|Noel J|NJ|
Lakshminrusimha|Satyan|S|
Goniewicz|Maciej L|ML|

D066300:Electronic Nicotine Delivery Systems

immature lung
toxicity
electronic cigarette flavorings
electronic cigarettes
lung development


Biotechnological Advances in the Design of Algae-Based Biosensors.

Abstract: In addition to their use in biomass production and bioremediation, algae have been extensively exploited in biosensing applications. Algae-based biosensors have demonstrated potential for sensitive, sustainable, and multiplexed detection of analytes of agroenvironmental and security interest. Their advantages include the availability of different algal bioreceptors including whole cells and their photosynthetic subcomponents, their potential to be integrated into dual transduction miniaturized devices, and the opportunity for continuous environmental monitoring. Despite obstacles including limited stability and selectivity, algae-based biosensing is a realistic prospect that has some recent effective applications. Strategic exploitation of cutting-edge technologies including materials science, nanotechnology, microfluidics, and genome editing will help to achieve the full potential of algae-based sensors.

artificial bioinspired receptors
lab-on-a-chip diagnostics
nanomaterials
paper-based biosensors
photosynthetic algae


Molecular Epidemiology of Third-Generation-Cephalosporin-Resistant Enterobacteriaceae in Southeast Queensland, Australia.

Abstract: Third-generation cephalosporin-resistant (3GC-R) Enterobacteriaceae represent a major threat to human health. Here, we captured 288 3GC-R Enterobacteriaceae clinical isolates from 264 patients presenting at a regional Australian hospital over a 14-month period. In addition to routine mass spectrometry and antibiotic sensitivity testing, isolates were examined using rapid (∼40-min) real-time PCR assays targeting the most common extended-spectrum β-lactamases (ESBLs; bla CTX-M-1 and bla CTX-M-9 groups, plus bla TEM, bla SHV, and an internal 16S rRNA gene control). AmpC CMY β-lactamase (bla CMY) prevalence was also examined. Escherichia coli (80.2%) and Klebsiella pneumoniae (17.0%) were dominant, with Klebsiella oxytoca, Klebsiella aerogenes, and Enterobacter cloacae infrequently identified. Ceftriaxone and cefoxitin resistance were identified in 97.0% and 24.5% of E. coli and K. pneumoniae isolates, respectively. Consistent with global findings in Enterobacteriaceae, most (98.3%) isolates harbored at least one β-lactamase gene, with 144 (50%) harboring bla CTX-M-1 group, 92 (31.9%) harboring bla CTX-M-9 group, 48 (16.7%) harboring bla SHV, 133 (46.2%) harboring bla TEM, and 34 (11.8%) harboring bla CMY genes. A subset of isolates (n = 98) were subjected to whole-genome sequencing (WGS) to identify the presence of cryptic resistance determinants and to verify genotyping accuracy. WGS of β-lactamase-negative or carbapenem-resistant isolates identified uncommon ESBL and carbapenemase genes, including bla NDM and bla IMP, and confirmed all PCR-positive genotypes. We demonstrate that our PCR assays enable the rapid and cost-effective identification of ESBLs in the hospital setting, which has important infection control and therapeutic implications.

Stewart|A G|AG|
Price|E P|EP|0000-0002-1079-4882
Schabacker|K|K|
Birikmen|M|M|
Harris|P N A|PNA|0000-0002-2895-0345
Choong|K|K|
Subedi|S|S|
Sarovich|D S|DS|0000-0002-6944-3980

Enterobacteriaceae
antibiotic
real-time PCR
ESBL
resistance
whole-genome sequencing
antimicrobial
cephalosporin
diagnostics


The perils of inhibiting deficient factors.

Abstract:
Essentials Anticoagulation in patients with factor X deficiency is an evidence-poor area. A patient with factor X deficiency was anticoagulated with warfarin followed by rivaroxaban. Warfarin may be a safer anticoagulant option than rivaroxaban in hereditary factor X deficiency. A baseline coagulation screen should be performed prior to commencement of anticoagulation.

SUMMARY
We report a case of a previously undiagnosed factor X deficiency in an 83-year-old man who had no previous bleeding history despite multiple hemostatic challenges. He was anticoagulated with warfarin for atrial fibrillation without bleeding complications; however, major hemorrhage occurred soon after a switch to rivaroxaban.

factor X
rivaroxaban
coagulation
oral anticaogulants
pharmacotherapeutics


Who can tolerate a marginal kidney? Predicting survival after deceased donor kidney transplant by donor-recipient combination.

Abstract: The impact of donor quality on post-kidney transplant (KT) survival may vary by candidate condition. Characterizing this variation would increase access to KT without sacrificing outcomes. We developed a tool to estimate post-KT survival for combinations of donor quality and candidate condition. We studied deceased donor KT recipients (n = 120 818) and waitlisted candidates (n = 376 272) between 2005 and 2016 by using the Scientific Registry of Transplant Recipients. Donor quality and candidate condition were measured by using the Kidney Donor Profile Index (KDPI) and the Estimated Post Transplant Survival (EPTS) score. We estimated 5-year post-KT survival based on combinations of KDPI and EPTS score using random forest algorithms and waitlist survival by EPTS score using Weibull regressions. Survival benefit was defined as absolute reduction in mortality risk with KT. For candidates with an EPTS score of 80, 5-year waitlist survival was 47.6%, and 5-year post-KT survival was 78.9% after receiving kidneys with a KDPI of 20 and was 70.7% after receiving kidneys with a KDPI of 80. The impact of KDPI on survival benefit varied greatly by EPTS score. For candidates with low EPTS scores (eg, <40), the KDPI had limited impact on survival benefit. For candidates with middle or high EPTS scores (eg, >40), survival benefit decreased with higher KDPI but was still substantial even with a KDPI of 100 (>16 percentage points). Our prediction tool (www.transplantmodels.com/kdpi-epts) can support individualized decision-making on kidney offers in clinical practice.

Bae|Sunjae|S|0000-0003-0098-8816
Massie|Allan B|AB|
Thomas|Alvin G|AG|0000-0003-4911-8192
Bahn|Gahyun|G|
Luo|Xun|X|
Jackson|Kyle R|KR|
Ottmann|Shane E|SE|
Brennan|Daniel C|DC|
Desai|Niraj M|NM|
Coresh|Josef|J|
Segev|Dorry L|DL|
Garonzik Wang|Jacqueline M|JM|

clinical decision-making
clinical research/practice
epidemiology
kidney transplantation/nephrology
organ acceptance
registry/registry analysis


Minimal contribution of the hepatic uptake transporter OATP1B1 to the inter-individual variability in SN-38 pharmacokinetics in cancer patients without severe renal failure.

Abstract:
PURPOSE
SN-38, a pharmacologically active metabolite of irinotecan, is taken up into hepatocytes by organic anion transporting polypeptide (OATP) 1B1. The effects of functional OATP1B1 521T>C on the pharmacokinetics of SN-38 remain controversial. Here, we prospectively examined the effects of OATP1B1 function on the area under the plasma total or unbound concentration-time curve (tAUC or uAUC) of SN-38 by assessing OATP1B1 521T>C and the plasma levels of endogenous OATP1B1 substrates, coproporphyrin (CP)-I and III, in cancer patients treated with irinotecan.

METHODS
We enrolled cancer patients who were treated with an irinotecan-containing regimen and did not have severe renal failure. The total and unbound concentrations of SN-38 in the plasma were measured by high-performance liquid chromatography. AUC values were calculated and normalized to the actual irinotecan dose (AUC/dose). The OATP1B1 521T>C was analyzed by direct sequencing. Concentrations of the endogenous substrates in plasma before irinotecan treatment (baseline) were determined by liquid chromatography with tandem mass spectrometry.

RESULTS
Twenty-two patients with a median estimated glomerular filtration rate of 74.8 mL/min (range 32.6-99.6) were examined. Both tAUC/dose and uAUC/dose were associated with the grade of neutropenia; however, they were not associated with OATP1B1 521T>C or baseline CP-I and III levels. It is worth noting that these baseline concentrations were significantly higher in patients with OATP1B1 521C, supporting functional changes in OATP1B1.

CONCLUSION
The contribution of OATP1B1 activity to inter-patient variability in the systemic exposure to SN-38 is likely minimal in patients without severe renal failure.

Tsuboya|Ayako|A| Kubota|Yutaro|Y| Ishida|Hiroo|H| Ohkuma|Ryotaro|R| Ishiguro|Tomoyuki|T| Hirasawa|Yuya|Y| Ariizumi|Hirotsugu|H| Tsunoda|Takuya|T| Sasaki|Yasutsuna|Y| Matsumoto|Natsumi|N| Kondo|Yusuke|Y| Tomoda|Yukana|Y| Kusuhara|Hiroyuki|H| Fujita|Ken-Ichi|KI|0000-0002-1575-6690

D027381:Liver-Specific Organic Anion Transporter 1


Development and validation of next generation sequencing based 35-gene hereditary cancer panel.

Abstract:
Background
Understanding the genetic basis of cancer risk is a major international endeavor. The emergence of next-generation sequencing (NGS) in late 2000's has further accelerated the discovery of many cancer susceptibility genes. The use of targeted NGS-based multigene testing panels to provide comprehensive analysis of cancer susceptible genes has proven to be a viable option, with the accurate and robust detection of a wide range of clinically relevant variants in the targeted genes being crucial.

Methods
We have developed and validated a targeted NGS-based test for hereditary cancer risk assessment using Illumina's NGS platform by analyzing the protein-coding regions of 35 hereditary cancer genes with a bioinformatics pipeline that utilizes standard practices in the field. This 35-gene hereditary cancer panel is designed to identify germline cancer-causing mutations for 8 different cancers: breast, ovarian, prostate, uterine, colorectal, pancreatic, stomach cancers and melanoma. The panel was validated using well-characterized DNA specimens [NIGMS Human Genetic Cell Repository], where DNA had been extracted using blood of individuals whose genetic variants had been previously characterized by the 1000 Genome Project and the Coriell Catalog.

Results
The 35-gene hereditary cancer panel shows high sensitivity (99.9%) and specificity (100%) across 4820 variants including single nucleotide variants (SNVs) and small insertions and deletions (indel; up to 25 bp). The reproducibility and repeatability are 99.8 and 100%, respectively.

Conclusions
The use of targeted NGS-based multigene testing panels to provide comprehensive analysis of cancer susceptible genes has been considered a viable option. In the present study, we developed and validated a 35-gene panel for testing 8 common cancers using next-generation sequencing (NGS). The performance of our hereditary cancer panel is assessed across a board range of variants in the 35 genes to support clinical use.

Chan|Wing|W|
Lee|Mianne|M|
Yeo|Zhen Xuan|ZX|
Ying|Dingge|D|
Grimaldi|Keith A|KA|
Pickering|Craig|C|
Yang|Michael M S|MMS|
Sundaram|Senthil K|SK|
Tzang|Lawrence C H|LCH|

Next generation sequencing
Hereditary cancer
Analytical validation
Genetic testing
Multigene panel testing


Diagnosis and treatment of patients with antiphospholipid syndrome: a mixed-method evaluation of care in The Netherlands.

Abstract:
Objectives
The aims were to gain insight into the care provided to patients with APS in The Netherlands and to identify areas for improvement from the perspective of both patients and medical specialists.

Methods
APS care was evaluated using qualitative and quantitative methods. Perspectives on APS care were explored using semi-structured interviews with medical specialists, patient focus groups and a cross-sectional, online patient survey. In order to assess current practice, medical records were reviewed retrospectively to collect data on clinical and laboratory manifestations and pharmacological treatment in six Dutch hospitals.

Results
Fourteen medical specialists were interviewed, 14 patients participated in the focus groups and 79 patients completed the survey. Medical records of 237 patients were reviewed. Medical record review showed that only one-third of patients were diagnosed with APS within 3 months after entering specialist care. The diagnostic approach and management varied between centres and specialists. Almost 10% of all patients and 7% of triple-positive patients with thrombotic APS were not receiving any anticoagulant treatment at the time of medical record review. Correspondingly, poor recognition and fragmentation of care were reported as the main problems by medical specialists. Additionally, patients reported the lack of accessible, reliable patient education, psychosocial support and trust in physicians as important points for improvement.

Conclusion
Delayed diagnosis, variability in management strategies and fragmentation of care were important limitations of APS care identified in this study. A remarkable 10% of patients did not receive any anticoagulant treatment.

antiphospholipid syndrome
medical records
qualitative research
quality of care
unmet patient needs


Radiobiological effects of the interruption time with Monte Carlo Simulation on multiple fields in photon beams.

Abstract:
PURPOSE
The interruption time is the irradiation interruption that occurs at sites and operations such as the gantry, collimator, couch rotation, and patient setup within the field in radiotherapy. However, the radiobiological effect of prolonging the treatment time by the interruption time for tumor cells is little evaluated. We investigated the effect of the interruption time on the radiobiological effectiveness with photon beams based on a modified microdosimetric kinetic (mMK) model.

METHODS
The dose-mean lineal energy yD (keV/µm) of 6-MV photon beams was calculated by the particle and heavy ion transport system (PHITS). We set the absorbed dose to 2 or 8 Gy, and the interruption time (τ) was set to 1, 3, 5, 10, 30, and 60 min. The biological parameters such as α0, β0, and DNA repair constant rate (a + c) values were acquired from a human non-small-cell lung cancer cell line (NCI-H460) for the mMK model. We used two-field and four-field irradiation with a constant dose rate (3 Gy/min); the photon beams were paused for interruption time τ. We calculated the relative biological effectiveness (RBE) to evaluate the interruption time's effect compared with no interrupted as a reference.

RESULTS
The yD of 6-MV photon beams was 2.32 (keV/µm), and there was little effect by changing the water depth (standard deviation was 0.01). The RBE with four-field irradiation for 8 Gy was decreased to 0.997, 0.975, 0.900, and 0.836 τ = 1, 10, 30, 60 min, respectively. In addition, the RBE was affected by the repair constant rate (a + c) value, the greater the decrease in RBE with the longer the interruption time when the (a + c) value was large.

CONCLUSION
The ~10-min interruption of 6-MV photon beams did not significantly impact the radiobiological effectiveness, since the RBE decrease was <3%. Nevertheless, the RBE's effect on tumor cells was decreased about 30% by increasing the 60 min interruption time at 8 Gy with four-field irradiation. It is thus necessary to make the interruption time as short as possible.

Nakano|Hisashi|H| Kawahara|Daisuke|D| Tanabe|Satoshi|S| Utsunomiya|Satoru|S| Takizawa|Takeshi|T| Sakai|Madoka|M| Saito|Hirotake|H| Ohta|Atsushi|A| Kaidu|Motoki|M| Ishikawa|Hiroyuki|H|

interruption time
Monte Carlo simulation
external photon beam
microdosimetric kinetic model
sublethal damage repair


Polymer Simulations of Heteromorphic Chromatin Predict the 3D Folding of Complex Genomic Loci.

Abstract: Chromatin folded into 3D macromolecular structures is often analyzed by chromosome conformation capture (3C) and fluorescence in situ hybridization (FISH) techniques, but these frequently provide contradictory results. Chromatin can be modeled as a simple polymer composed of a connected chain of units. By embedding data for epigenetic marks (H3K27ac), chromatin accessibility (assay for transposase-accessible chromatin using sequencing [ATAC-seq]), and structural anchors (CCCTC-binding factor [CTCF]), we developed a highly predictive heteromorphic polymer (HiP-HoP) model, where the chromatin fiber varied along its length; combined with diffusing protein bridges and loop extrusion, this model predicted the 3D organization of genomic loci at a population and single-cell level. The model was validated at several gene loci, including the complex Pax6 gene, and was able to determine locus conformations across cell types with varying levels of transcriptional activity and explain different mechanisms of enhancer use. Minimal a priori knowledge of epigenetic marks is sufficient to recapitulate complex genomic loci in 3D and enable predictions of chromatin folding paths.

Buckle|Adam|A|
Brackley|Chris A|CA|
Boyle|Shelagh|S|
Marenduzzo|Davide|D|
Gilbert|Nick|N|

D017404:In Situ Hybridization, Fluorescence

D012045:Regulatory Sequences, Nucleic Acid

chromatin
3C
FISH
transcription
enhancer
Capture-C
genome organization
histone modifications
polymer modeling


Linkage disequilibrium mapping for grain Fe and Zn enhancing QTLs useful for nutrient dense rice breeding.

Abstract:
BACKGROUND
High yielding rice varieties are usually low in grain iron (Fe) and zinc (Zn) content. These two micronutrients are involved in many enzymatic activities, lack of which cause many disorders in human body. Bio-fortification is a cheaper and easier way to improve the content of these nutrients in rice grain.

RESULTS
A population panel was prepared representing all the phenotypic classes for grain Fe-Zn content from 485 germplasm lines. The panel was studied for genetic diversity, population structure and association mapping of grain Fe-Zn content in the milled rice. The population showed linkage disequilibrium showing deviation of Hardy-Weinberg's expectation for Fe-Zn content in rice. Population structure at K = 3 categorized the panel population into distinct sub-populations corroborating with their grain Fe-Zn content. STRUCTURE analysis revealed a common primary ancestor for each sub-population. Novel quantitative trait loci (QTLs) namely qFe3.3 and qFe7.3 for grain Fe and qZn2.2, qZn8.3 and qZn12.3 for Zn content were detected using association mapping. Four QTLs, namely qFe3.3, qFe7.3, qFe8.1 and qFe12.2 for grain Fe content were detected to be co-localized with qZn3.1, qZn7, qZn8.3 and qZn12.3 QTLs controlling grain Zn content, respectively. Additionally, some Fe-Zn controlling QTLs were co-localized with the yield component QTLs, qTBGW, OsSPL14 and qPN. The QTLs qFe1.1, qFe3.1, qFe5.1, qFe7.1, qFe8.1, qZn6, qZn7 and gRMm9-1 for grain Fe-Zn content reported in earlier studies were validated in this study.

CONCLUSION
Novel QTLs, qFe3.3 and qFe7.3 for grain Fe and qZn2.2, qZn8.3 and qZn12.3 for Zn content were detected for these two traits. Four Fe-Zn controlling QTLs and few yield component QTLs were detected to be co-localized. The QTLs, qFe1.1, qFe3.1, qFe5.1, qFe7.1, qFe8.1, qFe3.3, qFe7.3, qZn6, qZn7, qZn2.2, qZn8.3 and qZn12.3 will be useful for biofortification of the micronutrients. Simultaneous enhancement of Fe-Zn content may be possible with yield component traits in rice.

Pradhan|S K|SK|
Pandit|E|E|
Pawar|S|S|
Naveenkumar|R|R|
Barik|S R|SR|
Mohanty|S P|SP|
Nayak|D K|DK|
Ghritlahre|S K|SK|
Sanjiba Rao|D|D|
Reddy|J N|JN|
Patnaik|S S C|SSC|

Linkage disequilibrium
Grain Fe content
Grain Zn content
Biofortification
Association study


CCR4+ Skin-Tropic Phenotype as a Feature of Central Memory CD8+ T Cells in Healthy Subjects and Psoriasis Patients.

Abstract: The chemokine receptor CCR4 has emerged as a skin-homing molecule important for the migration of T cells from the blood to the dermis. From our previous data on psoriasis patients, CCR4+ memory T cells emerged as a putative recirculating population between skin and blood. Here we focused our attention on the expression of CCR4 and skin-tropic molecules in the different stages of memory T cell differentiation. We analyzed the chemokine receptor profile in CD8+ and CD4+ CD45RA-CCR7+ (TCM) and CD45RA-CCR7- (TEM) cells. Subpopulations were further divided on the basis of CD62L expression, and the distribution among the subsets of the skin-homing molecule CLA (Cutaneous Lymphocyte Antigen) was evaluated. The characterization was performed on peripheral blood mononuclear cells isolated from 21 healthy subjects and 24 psoriasis patients. The results indicate that (i) the skin-homing CCR4 marker is mainly expressed in TCM cells, (ii) CCR4+ TCM cells also express high level of CLA and that (iii) the more differentiated phenotype TEM expresses CXCR3 and CCR5 but lower level of CCR4 and CLA. This indicates that progressive stages of memory T cell differentiation have profoundly different chemokine receptor patterns, with CD8+ TCM displaying a marked skin-tropic phenotype CLA+CCR4+. Differential skin-tropic phenotype between TCM and TEM cells was observed in both healthy subjects and psoriasis patients. However, patients showed an expanded circulating population of CD8+ TCM cells with phenotype CCR4+CXCR3+ that could play a role in the pathophysiology of psoriasis and possibly in disease recurrence.

Casciano|Fabio|F| Diani|Marco|M| Altomare|Andrea|A| Granucci|Francesca|F| Secchiero|Paola|P| Banfi|Giuseppe|G| Reali|Eva|E|

central memory
T cells
skin
effector memory
psoriatic disease
tissue immunosurveillance


Prosthetic management of an extensive maxillary alveolar defect with an implant-supported restoration.

Abstract: Despite the recent developments in peri-implant surgical regenerative procedures, re-establishing the hard and soft tissue contour is still a challenge in cases with severe ridge deficiency. It becomes more difficult when incorrectly placed implants cause screw connections to come out onto the labial surfaces of the teeth. A two-part maxillary implant supported fixed restoration was constructed. The first part was consisted of a screw retained sub-structure that replaced gingival portions of the deficient maxilla and the second part was a cement retained super-structure that reconstructed the anatomical crowns of the lost teeth. In this way awkwardly placed implants did not interfere with the desired esthetic result. Another great advantage was that the alterations or repairs on cemented crowns can easily be carried out without compromising the entire construction.

Implant-Supported
Maxilla
Dental Implants
Dental Prosthesis
Dental Porcelain


Aromatase Blockade Is Associated With Increased Mortality in Acute Illness in Male Mice.

Abstract:
Context
The increase in circulating estrogen levels with acute illness in humans is accompanied by increased aromatase expression in adipose tissue and increased peripheral aromatization of estrogens to androgens. Animal studies indicate that estrogen may be beneficial in acute illness.

Objective
We hypothesized that blockade of aromatase in acute illness would decrease survival.

Design
Prospective sham controlled.

Setting
Maine Medical Center Research Institute animal facility.

Animals
Six- to 8-week-old male black 6 mice.

Intervention
Mice underwent cecal ligation and puncture (CLP) to induce acute illness and were administered letrozole to block aromatase or saline. Mice undergoing sham surgery with or without letrozole served as controls. Adipose and cardiovascular tissue was harvested for preliminary evaluation of aromatase expression.

Main outcome measurements
Survival was the main outcome measurement. Evidence for aromatase expression in tissue samples was assessed using western blot and/or immunohistochemistry.

Results
With aromatase blockade, survival in CLP mice was decreased (P = 0.04). The presence of aromatase in adipose tissue was observed by western blot in CLP but not control mice. Similarly, the presence of aromatase was observed in cardiac tissue of CLP but not in control mice.

Conclusions
The decreased survival during sepsis with aromatase blockade suggests that this response to acute illness may be important both physiologically and clinically. The preliminary observation of aromatase expression in adipose and cardiovascular tissue during acute illness in this mouse model indicates that this model has parallels to human physiology and may be useful for further studying the aromatase response to acute illness.

Connerney|Jeannette J|JJ|
Spratt|Daniel I|DI|

aromatase blockade
acute illness
survival


Effects of Long-Duration Spaceflight on Vertebral Strength and Risk of Spine Fracture.

Abstract: Although the negative impact of long-duration spaceflight on spine BMD has been reported, its impact on vertebral strength and risk of vertebral fracture remains unknown. This study examined 17 crewmembers with long-duration service on the International Space Station in whom computed tomography (CT) scans of the lumbar spine (L1 and L2 ) were collected preflight, immediately postflight and 1 to 4 years after return to Earth. We assessed vertebral strength via CT-based finite element analysis (CT-FEA) and spinal loading during different activities via subject-specific musculoskeletal models. Six months of spaceflight reduced vertebral strength by 6.1% (-2.3%, -8.7%) (median [interquartile range]) compared to preflight (p < 0.05), with 65% of subjects experiencing deficits of greater than 5%, and strengths were not recovered up to 4 years after the mission. This decline in vertebral strength exceeded (p < 0.05) the 2.2% (-1.3%, -6.0%) decline in lumbar spine DXA-BMD. Further, the subject-specific changes in vertebral strength were not correlated with the changes in DXA-BMD. Although spinal loading increased slightly postflight, the ratio of vertebral compressive load to vertebral strength for typical daily activities remained well below a value of 1.0, indicating a low risk of vertebral fracture despite the loss in vertebral strength. However, for more strenuous activity, the postflight load-to-strength ratios ranged from 0.3 to 0.7, indicating a moderate risk of vertebral fracture in some individuals. Our findings suggest persistent deficits in vertebral strength following long-duration spaceflight, and although risk of vertebral fracture remains low for typical activities, the risk of vertebral fracture is notable in some crewmembers for strenuous exercise requiring maximal effort. © 2019 American Society for Bone and Mineral Research.

Burkhart|Katelyn|K|0000-0003-4030-049X
Allaire|Brett|B|
Anderson|Dennis E|DE|
Lee|David|D|
Keaveny|Tony M|TM|
Bouxsein|Mary L|ML|0000-0002-7027-7414

D015519:Bone Density
D020342:Finite Element Analysis
D006801:Humans
D008159:Lumbar Vertebrae
D013026:Space Flight
D016103:Spinal Fractures
D013131:Spine

spaceflight
vertebral strength
spinal loading
bone QCT
vertebral fracture risk assessment


Pd-Catalyzed, Ligand-Enabled Stereoselective 1,2-Iodine(III) Shift/1,1-Carboxyalkynylation of Alkynylbenziodoxoles.

Abstract: A PdII -catalyzed 2:1 coupling reaction of alkynylbenziodoxole with carboxylic acid to afford (alk-1-en-3-ynyl)benziodoxole, which is efficiently promoted by an octahydrophenazine ligand, is reported. The reaction involves a Pd-assisted 1,2-iodine(III) shift of the alkynylbenziodoxole followed by stereoselective introduction of carboxy and alkynyl groups (the latter originating from another molecule of the alkynylbenziodoxole) into the 1-position of the transient Pd-vinylidene species. The product of this 1,1-carboxyalkynylation reaction serves as a new functionalized enyne-type building block for further synthetic transformations.

carboxylic acid
alkynylation
cross-coupling
hypervalent iodine
palladium


Inhabiting the Body(ies) in Female Soccer Players: The Protective Role of Positive Body Image.

Abstract: In a social and sports world dominated by weight-centred beliefs and highly exigent and gendered athletic and beauty body standards, the vulnerability for eating pathology, i.e., disordered eating and eating disorders (EDs), is elevated among women athletes. The aim of this study was to explore body image facets and ED risk among female athletes in masculinised sports such as soccer. Forty-five federated amateur female soccer players from Spain participated in this study, voluntarily complying with an extensive evaluation protocol on attitudes towards body and appearance and eating practises. The participants overall reported self-representations of their bodies that corresponded to their reality as athletes, but their body ideals were also more demanding in terms of low fat and muscularity, in association with the functionality of their body and the physical demands of their athletic activity. Despite having a fairly high positive body image and body satisfaction, they also expressed negative attitudes towards their bodies. Around 2 out of 10 players were at risk of suffering from an ED. Players with negative attitudes towards their bodies had an odd 12 times likely to develop an ED compared to those with lower self-devaluation, after adjusting for BMI and body perceptions (OR = 12.3, p < 0.01). On the contrary, players who appreciate their bodies and hold a positive body image had an odd 83% lower to suffer from eating pathology, after adjusting for BMI and body satisfaction (OR = 0.17, p < 0.05). Our findings support the healthy and protective role of positive body image in sports contexts. Body attitudes should be addressed in preventive and therapeutic efforts for reducing the prevalence of EDs in women's sports, within both a "negative" and a "positive" paradigm of body image.

body image
gender
eating pathology
women
body positivity
feminist sport psychology
soccer (football)


Gene editing of stem cells for kidney disease modelling and therapeutic intervention.

Abstract: Recent developments in targeted gene editing have paved the way for the wide adoption of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein-9 nucleases (Cas9) as an RNA-guided molecular tool to modify the genome of eukaryotic cells of animals. Theoretically, the translation of CRISPR-Cas9 can be applied to the treatment of inherited or acquired kidney disease, kidney transplantation and genetic corrections of somatic cells from kidneys with inherited mutations, such as polycystic kidney disease. Human pluripotent stem cells have been used to generate an unlimited source of kidney progenitor cells or, when spontaneously differentiated into three-dimensional kidney organoids, to model kidney organogenesis or the pathogenesis of disease. Gene editing now allows for the tagging and selection of specific kidney cell types or disease-specific gene knock in/out, which enables more precise understanding of kidney organogenesis and genetic diseases. This review discusses the mechanisms of action, in addition to the advantages and disadvantages, of the three major gene editing technologies, namely, CRISPR-Cas9, zinc finger nucleases and transcription activator-like effector nucleases. The implications of using gene editing to better understand kidney disease is reviewed in detail. In addition, the ethical issues of gene editing, which could be easily neglected in the modern, fast-paced research environment, are highlighted.

Lau|Ricky Wk|RW|
Wang|Bo|B|
Ricardo|Sharon D|SD|

D000818:Animals
D064113:CRISPR-Cas Systems
D000072669:Gene Editing
D015316:Genetic Therapy
D006801:Humans
D007674:Kidney Diseases
D013234:Stem Cells

gene editing
stem cells
CRISPR-Cas9
mutations
gene corrections
inherited kidney disease


GPIb-IX-V and platelet clearance.

Abstract: Platelet adhesion to the site of vascular damage is a critical early step in hemostasis. The platelet glycoprotein (GP) Ib-IX-V plays a key role in this step via its interaction with immobilized von Willebrand Factor (VWF). In addition to its well-known role in adhesion, GPIb-IX-V is critical for platelets' survival in circulation and plays an important role in the regulation of platelet clearance. Several mechanisms of platelet clearance work in concert to maintain a normal platelet count and ensure that circulating platelets are functionally viable via removal of senescent or activated platelets. Furthermore, dysregulation of platelet clearance underlies several bleeding disorders. GPIb-IX-V is central to many physiological mechanisms of platelet clearance including clearance via glycan receptors, clearance of VWF-platelet complexes, and fast clearance of transfused platelets. GPIb-IX-V dependent clearance also underlies thrombocytopenia in several bleeding disorders, including von Willebrand disease (VWD) and immune thrombocytopenia. This review will cover physiological and pathological mechanisms of platelet clearance, focusing on the role of GPIb-IX-V.

platelet clearance
glycans
thrombocytopenia
GPIb-IX
platelet storage


The effects of foam roll on perceptual and performance recovery during a futsal tournament.

Abstract: The present study investigated the efficacy of recovery by foam rolling (FR) on performance, psychological, and physiological parameters of futsal players in a simulated futsal tournament. In this randomized controlled trial design, four youth teams from Iran's national premier league participated in a simulated futsal tournament (five days, three matches). Sixteen youth futsal players from two teams (age: 19.1 ± 1.3 years old) were randomly distributed into two groups: (i) passive recovery (PR); and (ii) FR recovery. The FR recovery protocol consisted of five repetitions of 40 s separated by 20 s of rest on calf, quadriceps, hamstrings, and gluteus muscles 5 min after each match. The other group rested passively during the same period. The Yo-Yo intermittent recovery level 2, repeated sprint ability, vertical jump, and PRO agility tests were assessed pre- and post-tournament. Also, Hooper index (HI) and blood lactate concentrations were measured throughout matchdays. Data were analyzed by a repeated measure ANOVA and ANCOVA. Substantial improvements in HI on the second (ES:0.6) and third (ES:0.4) matchdays and faster lactate removal on the third (ES:0.3) matchday were observed in the FR group when compared to the PR group (p<0.05). Although FR recovery was slightly beneficial when compared to PR attenuated decrements in aerobic (-1.6%vs-9.7%) and anaerobic performance (-4.5%vs-1.3%), vertical jump (-1.6%vs-3.0%), and change of direction (-2.1%vs-4.3%), these effects were not statistically significant (p>0.05). The finding showed using FR during compact competitions expedites physical performance recovery, increases blood lactate clearance and leads to regenerate psychological characteristics. Therefore, along with other desirable recovery strategies, the use of FR could be recommended in short-term compacted futsal tournaments.

Rahimi|Ali|A|
Amani-Shalamzari|Sadegh|S|
Clemente|Filipe Manuel|FM|

Performance Football Neuromuscular Readiness Well-being


Isometric strength of the hip abductors and external rotators in athletes with and without patellar tendinopathy.

Abstract:
PURPOSE
This study aims to compare the isometric strength of hip abductors and external rotators in male athletes with and without patellar tendinopathy (PT), and to examine the correlation between hip strength, pain, and functional scores.

METHODS
Sixty male athletes (30 with PT and 30 controls) were recruited from local volleyball and basketball teams. The isometric strength of the hip abductors and external rotators was quantified using a belt-stabilized handheld dynamometer. This study used the visual analog scale (VAS) and the Victorian Institute of Sport Assessment-Patella (VISA-p) questionnaire to measure the intensity of pain and functional scores in athletes with PT, respectively.

RESULTS
The normalized isometric strength of the hip abductors and external rotators was significantly less in the PT group compared with controls. In subjects with PT, the normalized isometric strength was decreased by 22.0% (p = 0.000) in the hip abductors and by 20.0% in the hip external rotators (p = 0.004), compared with controls. Significant correlations were found between the normalized isometric strength of the hip abductors and intensity of pain (r = - 0.70; p < 0.05) and VISA-p score (r = 0.63; p < 0.05) in the affected leg in athletes with unilateral PT.

CONCLUSIONS
Athletes with PT have decreased isometric strength in their hip abductors and external rotators when compared with controls. In subjects with unilateral PT, decreased isometric strength in the hip abductors is associated with greater intensity of pain and lower functional scores. Results of this study implied that hip muscle assessment and strengthening should be included for reconditioning and rehabilitation in athletes with PT.

Zhang|Z J|ZJ|
Lee|W C|WC|
Ng|G Y F|GYF|
Fu|S N|SN|

Basketball and volleyball players
Isometric strength of the hip muscles
Landing kinematics


Immune sensing of DNA and strategies for fish DNA vaccine development.

Abstract: Studies of DNA vaccines have shown that understanding the mechanism of DNA vaccine-mediated action is the key for vaccine development. Current knowledge has shown the presence of antigen presenting cells (APCs) involving in B and T cells at the muscle injection site and the upregulation of type I interferon (IFN-I) that initiates antiviral response and benefits adaptive immunity in fish DNA vaccines. IFN-I may be triggered by expressed antigen such as the rhabdovirus G protein encoded DNA vaccine or by plasmid DNA itself through cytosolic DNA sensing. The investigating of Toll-like receptor 9, and 21 are the CpG-motif sensors in many fish species, and the cytosolic DNA receptors DDX41 and downstream STING signaling revealed the mechanisms for IFN-I production. This review article describes the recent finding of receptors for cytosolic DNA, the STING-TBK1-IRF signaling, and the possibility of turning these findings into strategies for the future development of DNA vaccines.

D000818:Animals
D001424:Bacterial Infections
D001428:Bacterial Vaccines
D005393:Fish Diseases
D007370:Interferon Type I
D017471:Receptors, Interferon
D019444:Vaccines, DNA
D014765:Viral Vaccines
D014777:Virus Diseases


The anorexigenic effect of neuropeptide AF in Japanese quail, Coturnix japonica, is associated with activation of the melanocortin system.

Abstract: Neuropeptide AF (NPAF) decreases food and water intake in birds and food intake in mammals. In this study, the objective was to determine the effects of centrally administered NPAF on food and water intake, hypothalamic c-Fos immunoreactivity and hypothalamic mRNA abundance of appetite-regulating factors in Japanese quail (Coturnix japonica). Seven days post hatch, 6 h fasted quail were intracerebroventricularly (ICV) injected with 0 (vehicle), 4, 8, or 16 nmol of NPAF and food and water intake were measured at 30 min intervals for 180 min. In Experiment 1, chicks which received 4, 8, and 16 nmol ICV NPAF had reduced food intake for 120, 60 and 180 min following injection, respectively, and reduced water intake during the entire 180 min observation. In Experiment 2, there was increased c-Fos immunoreactivity in the paraventricular nucleus, the ventromedial nucleus of the hypothalamus, and the dorsomedial hypothalamic nucleus in NPAF-injected quail. In Experiment 3, ICV NPAF was associated with decreased corticotropin-releasing factor mRNA, and an increase in hypothalamic proopiomelanocortin and melanocortin receptor 4 mRNA. These results demonstrate that central NPAF suppresses food and water intake in quail, effects that are likely mediated via the melanocortin system in the hypothalamus.

Bohler|Mark|M|
Pauliukonis|Alex|A|
Gilbert|Elizabeth R|ER|
Cline|Mark A|MA|

Neuropeptide AF
Quail
Melanocortin
Hypothalamus
Corticotropin-releasing factor
Proopiomelanocortin
Appetite
Satiety


NAFLD fibrosis score (NFS) can be used in outpatient services to identify chronic vascular complications besides advanced liver fibrosis in type 2 diabetes.

Abstract: We demonstrate in 351 diabetic patients with steatosis that NAFLD fibrosis score (NFS), a rapid and affordable score to diagnose hepatic fibrosis, identifies patients at higher risk of advanced fibrosis and vascular diabetic complications (especially peripheral neuropathy), pointing NFS as a first-line vascular and hepatic screening in diabetic patients.

Lombardi|Rosa|R|
Airaghi|Lorena|L|
Targher|Giovanni|G|
Serviddio|Gaetano|G|
Maffi|Gabriele|G|
Mantovani|Alessandro|A|
Maffeis|Claudio|C|
Colecchia|Antonio|A|
Villani|Rosanna|R|
Rinaldi|Luca|L|
Orsi|Emanuela|E|
Pisano|Giuseppina|G|
Adinolfi|Luigi Elio|LE|
Fargion|Silvia|S|
Fracanzani|Anna Ludovica|AL|

D065626:Non-alcoholic Fatty Liver Disease

NAFLD
Diabetic neuropathy
Microvascular complications
Non-invasive diagnosis
Stroke
Type 2 diabetes screening


Clinical pharmacokinetics of magnesium sulfate in the treatment of children with severe acute asthma.

Abstract:
PURPOSE
Intravenous (IV) magnesium sulfate (MgSO4) is used as adjunct therapy to treat acute asthma exacerbations. Despite its clinical use, there is a limited understanding of the disposition of magnesium in children.

METHODS
To explore the pharmacokinetics (PK) of IV MgSO4 in this population, we collected retrospective data from 54 children who received IV MgSO4 for treatment of an acute asthma exacerbation at Primary Children's Hospital in Salt Lake City, UT. These data were analyzed using population PK modeling techniques in NONMEM® to determine sources of variability affecting the disposition of magnesium, as well as to predict the dose of IV MgSO4 needed to achieve clinical benefit.

RESULTS
The covariate analysis found that only weight was a significant predictor of magnesium concentrations in children. Estimated model parameters suggested that magnesium exhibits a short serum half-life (2.7 h) in children. The average endogenous magnesium concentration (prior to administration of IV MgSO4) was estimated to be 21 mg/L. Simulated data suggested that doses between 50 and 75 mg/kg are required to achieve concentration-time profiles within a hypothesized target therapeutic range between 25 and 40 mg/L.

CONCLUSIONS
These results provide new insight into the disposition of IV MgSO4 in children and provide dosing guidelines for future prospective studies of IV MgSO4 in children with acute asthma.

Rower|Joseph E|JE|
Liu|Xiaoxi|X|
Yu|Tian|T|
Mundorff|Michael|M|
Sherwin|Catherine M T|CM|
Johnson|Michael D|MD|

Acute asthma
Intravenous magnesium sulfate
Population pharmacokinetics
Serum magnesium


Radiomics signature of computed tomography imaging for prediction of survival and chemotherapeutic benefits in gastric cancer.

Abstract: To develop and validate a radiomics signature for the prediction of gastric cancer (GC) survival and chemotherapeutic benefits. In this multicenter retrospective analysis, we analyzed the radiomics features of portal venous-phase computed tomography in 1591 consecutive patients. A radiomics signature was generated by using the Lasso-Cox regression model in 228 patients and validated in internal and external validation cohorts. Radiomics nomograms integrating the radiomics signature were constructed, demonstrating the incremental value of the radiomics signature to the traditional staging system for individualized survival estimation. The performance of the nomograms was assessed with respect to calibration, discrimination, and clinical usefulness. The radiomics signature consisted of 19 selected features and was significantly associated with DFS (disease-free survival) and OS (overall survival). Multivariate analysis demonstrated that the radiomics signature was an independent prognostic factor. Incorporating the radiomics signature into the radiomics-based nomograms resulted in better performance for the estimation of DFS and OS than the clinicopathological nomograms and TNM staging system, with improved accuracy of the classification of survival outcomes. Further analysis showed that stage II and III patients with higher radiomics scores exhibited a favorable response to chemotherapy. In conclusion, the newly developed radiomics signature is a powerful predictor of DFS and OS, and it may predict which patients with stage II and III GC benefit from chemotherapy.

Jiang|Yuming|Y| Chen|Chuanli|C| Xie|Jingjing|J| Wang|Wei|W| Zha|Xuefan|X| Lv|Wenbing|W| Chen|Hao|H| Hu|Yanfeng|Y| Li|Tuanjie|T| Yu|Jiang|J| Zhou|Zhiwei|Z| Xu|Yikai|Y| Li|Guoxin|G|

D000971:Antineoplastic Combined Chemotherapy Protocols

Radiomics signature
Gastric cancer
Chemotherapy
Prognosis


Serum high-density lipoprotein cholesterol and progression to arterial stiffness in middle-aged and elderly Chinese.

Abstract:
BACKGROUND AND AIMS
Low high-density lipoprotein cholesterol (HDL-c) is a risk factor for cardiovascular disease. Brachial-ankle pulse wave velocity (baPWV) is an indicator of arterial stiffness, which is recognized as a predictor of cardiovascular disease. The aim of this study was to investigate the association between HDL-c and baPWV among middle-aged and elderly Chinese.

METHODS
A total number of 1133 Chinese (430 men, 703 women) aged from 50 to 90 years old were recruited from Shanghai downtown district. The baPWV and major cardiovascular risk factors of the participants were measured.

RESULTS
Serum HDL-c was negatively correlated with baPWV (r = -0.143, P < 0.001) after adjustment for age and gender. Multivariate linear regression analysis demonstrated that age (P < 0.001), systolic blood pressure (P < 0.001), HDL-c (P < 0.001), smoking (P = 0.001), BMI (P = 0.002), fasting plasma glucose (P = 0.004), and white blood cell (P = 0.005) were independently associated with baPWV. After multiple adjustments, participants in the highest quartile of HDL-c had an odds ratio of 0.442 (95% CI 0.268-0.729) for developing high arterial stiffness compared with participants in the lowest quartile. The association remained significant after further adjustment for major cardiovascular risk factors.

CONCLUSION
HDL-c has an independent protective effect on arterial stiffness in middle-aged and elderly Chinese. Early detection of HDL-c level is important in high risk populations with arterial stiffness. Increasing HDL-c level may be an attractive therapeutic target for the prevention of arterial function and subsequent disease.

Zhao|W W|WW|
Yang|Y H|YH|
Lu|B|B|
Feng|X C|XC|
He|M|M|
Yang|Z H|ZH|
Wen|J|J|
Zhang|Z Y|ZY|
Yang|Z|Z|
Li|Q|Q|
Ye|Z|Z|
Gong|W|W|
Hu|R M|RM|

High-density lipoprotein cholesterol (HDL-c)


Focus on the pedunculopontine nucleus. Consensus review from the May 2018 brainstem society meeting in Washington, DC, USA.

Abstract: The pedunculopontine nucleus (PPN) is located in the mesopontine tegmentum and is best delimited by a group of large cholinergic neurons adjacent to the decussation of the superior cerebellar peduncle. This part of the brain, populated by many other neuronal groups, is a crossroads for many important functions. Good evidence relates the PPN to control of reflex reactions, sleep-wake cycles, posture and gait. However, the precise role of the PPN in all these functions has been controversial and there still are uncertainties in the functional anatomy and physiology of the nucleus. It is difficult to grasp the extent of the influence of the PPN, not only because of its varied functions and projections, but also because of the controversies arising from them. One controversy is its relationship to the mesencephalic locomotor region (MLR). In this regard, the PPN has become a new target for deep brain stimulation (DBS) for the treatment of parkinsonian gait disorders, including freezing of gait. This review is intended to indicate what is currently known, shed some light on the controversies that have arisen, and to provide a framework for future research.

Garcia-Rill|E|E|
Saper|C B|CB|
Rye|David B|DB|
Kofler|M|M|
Nonnekes|J|J|
Lozano|A|A|
Valls-Solé|J|J|
Hallett|M|M|

Brainstem
Posture
Gait
Arousal
Basal ganglia
Blink reflex
CaMKII
Calcium channels
Gamma activity
N-type
P/Q-type
Prepulse inhibition
Sleep
Startle reflex
cAMP