Clinicopathologic features and prognosis of synchronous and metachronous multiple primary colorectal cancer.

Abstract:
PURPOSE
Multiple primary colorectal cancers (MPCCs) are different from solitary colorectal cancers in many aspects, which are not well studied. The aim of this study was to clarify the clinicopathological features and prognosis of MPCCs.

METHODS
The data of 64 patients with MPCCs out of 2300 patients with colorectal cancers (CRCs) from January 2009 to December 2017 were retrospectively analyzed. Stratified analysis was conducted based on subtypes and microsatellite status.

RESULTS
The overall incidence of MPCC was 2.8% and the median follow-up duration was 51.5 (range 1-120) months. Metachronous CRCs (MCRCs) are more likely to appear in the right colon (p < 0.05). However, no significant differences regarding age, sex, BMI, tumor size, smoking/drinking history, TNM stage, family history of cancer, and 5-year survival rate were observed between synchronous CRC (SCRC) and MCRC. Advanced TNM stage (III) and the presence of polyps were found to be independent poor prognostic factors for MPCCs. The prevalence of mismatch repair deficiency (dMMR) in MPCCs was 28.1%. Deficient MMR is more likely to appear in younger, lighter MPCC patients with polyps (p < 0.05). Of four mismatch repair proteins, MLH-1, MSH-2, MSH-6, and PMS-2 were negative in nine, nine, five, and nine patients, respectively. The 5-year survival rate did not differ significantly between MMR-proficient (pMMR) and dMMR groups (p = 0.752).

CONCLUSIONS
Synchronous CRC (SCRC) and MCRC might represent similar disease entities with different courses. Deficient MMR is more likely to appear in younger, lighter MPCC patients with polyps and it is an essential indicator for screening Lynch syndrome.

D000070976:Mismatch Repair Endonuclease PMS2

Synchronous
Metachronous
Multiple
Colorectal cancer
Microsatellite instability


Case Studies in Physiology: Untangling the cause of hypoxemia in a patient with obesity with acute leukemia.

Abstract: Diagnosing the cause of hypoxemia and dyspnea can be complicated in complex patients with multiple comorbidities. This "Case Study in Physiology" describes an man with obesity admitted to the hospital for relapse of acute lymphoblastic leukemia, who experienced progressive hypoxemia, shortness of breath, and dyspnea on exertion during his hospitalization. After initial empirical treatment with diuresis and antibiotics failed to improve his symptoms and because an arterial blood gas measurement was not readily available, we applied a novel, recently described physiological method to estimate the arterial partial pressure of oxygen from the peripheral saturation measurement and calculate the alveolar-arterial oxygen difference to discern the source of his hypoxemia and dyspnea. Using basic physiological principles, we describe how hypoventilation, anemia, and the use of a β blocker and furosemide, collaborated to create a "perfect storm" in this patient that impaired oxygen delivery and limited utilization. This case illustrates the application of innovative physiology methodology in medicine and provides a strong rationale for continuing to integrate physiology education in medical education.NEW & NOTEWORTHY Discerning the cause of dyspnea and hypoxemia in complex patients can be difficult. We describe the "real world" application of an innovative methodology to untangle the underlying physiology in a patient with multiple comorbidities. This case further demonstrates the importance of applying physiology to interrogate the underlying cause of a patient's symptoms when treatment based on probability fails.

Amaza|Iliya|I|
Kalra|Hardik|H|
Eberlein|Michael|M|
Jethava|Yogesh|Y|
McDonell|Joseph|J|
Wolfe|Bobby|B|
Tomasson|Michael H|MH|
Bates|Melissa L|ML|0000-0002-2605-0984

physiology education
A-aDO2
Hill equation
blood cancer
obesity hypoventilation syndrome


Expression and glycoengineering of functionally active heteromultimeric IgM in plants.

Abstract: IgM antibodies are an important player of the human's innate defense mechanisms and increasingly have gained interest as therapeutics. Although the expression of IgM antibodies in mammalian cell culture is established, this approach remains costly and alternative methods have not been developed yet. Plants have a proven record for the production of therapeutically relevant recombinant proteins. However, whether they are able to express proteins like IgM antibodies, which range among the most complex human proteins, remains unknown so far. Here we report the in planta generation of the functionally active monoclonal antitumor IgM PAT-SM6 (SM6). SM6 efficiently accumulates in plant leaves and assembles correctly into heterooligomers (pentamers and hexamers). Detailed glycosylation analysis exhibited complex and oligomannosidic N-glycans in a site-specific manner on human-serum IgM and on plant- and human-cell-line-produced SM6. Moreover, extensive in planta glycoengineering allowed the generation of SM6 decorated with sialylated human-type oligosaccharides, comparable to plasma-derived IgM. A glycosylated model of pentameric IgM exhibits different accessibility of the glycosylation sites, explaining site-specific glycosylation. Biochemical and biophysical properties and importantly biological activities of plant-derived SM6 glycoforms are comparable to the human-cell-derived counterparts. The in planta generation of one of the most complex human proteins opens new pathways toward the production of difficult-to-express proteins for pharmaceutical applications. Moreover, the generation of IgMs with a controlled glycosylation pattern allows the study of the so far unknown contribution of sugar moieties to the function of IgMs.

Loos|Andreas|A|
Gruber|Clemens|C|
Altmann|Friedrich|F|
Mehofer|Ulrich|U|
Hensel|Frank|F|
Grandits|Melanie|M|
Oostenbrink|Chris|C|
Stadlmayr|Gerhard|G|
Furtmüller|Paul G|PG|
Steinkellner|Herta|H|

D021241:Spectrometry, Mass, Electrospray Ionization


Signal-to-noise ratio of a mouse brain (13) C CryoProbe™ system in comparison with room temperature coils: spectroscopic phantom and in vivo results.

Abstract: MRI and MRS in small rodents demand very high sensitivity. Cryogenic transmit/receive radiofrequency probes (CryoProbes) designed for (1) H MRI of mouse brain provide an attractive option for increasing the performance of small-animal MR systems. As the Larmor frequency of (13) C nuclei is four times lower than that for (1) H nuclei, an even larger sensitivity improvement is expected for (13) C applications. The aim of this work was to evaluate the performance of a prototype (13) C CryoProbe™ for mouse brain MRS. To investigate the possible gain of the (13) C CryoProbe™, we acquired localized single-voxel (13) C spectra and chemical shift images of a dimethyl sulfoxide phantom with the CryoProbe™, as well as with two room temperature resonators. The cryogenically cooled resonator achieved approximately four-fold higher signal-to-noise ratio in phantom tests when compared with the best-performing room temperature coil. In addition, we present localized (13) C spectra of mouse brain obtained with the CryoProbe™, as well as with one of the room temperature coils, demonstrating the performance in vivo. In summary, the cryogenic cooling technique significantly enhances the (13) C signal sensitivity at 9.4 T and enables the investigation of metabolism within mouse brain.

Sack|M|M| Wetterling|F|F| Sartorius|A|A| Ende|G|G| Weber-Fahr|W|W|

mouse
CryoProbe™
MRS
13C spectroscopy
SNR comparison
cryogenic coil


The microvascular hypothesis underlying neurologic manifestations of long COVID-19 and possible therapeutic strategies.

Abstract: With the ongoing distribution of the coronavirus disease (COVID) vaccines, the pandemic of our age is ending, leaving the world to deal with its well-documented aftereffects. Long COVID comprises a variety of symptoms, of which the neurological component prevails. The most permeating theory on the genesis of these symptoms builds upon the development of microvascular dysfunction similar to that seen in numerous vascular diseases such as diabetes. This can occur through the peripheral activation of angiotensin-converting enzyme 2 receptors, or through exacerbations of pro-inflammatory cytokines that can remain in circulation even after the infection diminishes. Several drugs have been identified to act on the neurovascular unit to promote repair, such as gliptins, and others. They also succeeded in improving neurologic outcome in diabetic patients. The repurposing of such drugs for treatment of long COVID-19 can possibly shorten the time to recovery of long COVID-19 syndrome.

neurologic manifestations
long COVID-19
microvascular dysfunction
neurovascular regenerative drugs


Purification and characterization of cycloisomaltotetraose-forming glucanotransferases from Agreia sp. D1110 and Microbacterium trichothecenolyticum D2006.

Abstract: Glucanotransferases that can synthesize cyclo-{→6)-α-d-Glcp-(1→6)-α-d-Glcp-(1→6)-α-d-Glcp-(1→6)-α-d-Glcp-(1→} (CI4) from dextran were purified to homogeneity from the culture supernatant of Agreia sp. D1110 and Microbacterium trichothecenolyticum D2006. The molecular mass of both enzymes was estimated to be 86 kDa by SDS-PAGE. The glucanotransferase, named CI4-forming enzyme, from Agreia sp. exhibited the highest activity at pH 6.0 and 40 °C. The enzyme was stable on the pH range of 4.6-9.9 and up to 40 °C. On the other hand, the enzyme from M. trichothecenolyticum exhibited the highest activity at pH 5.7 and 40 °C. The enzyme was stable on the pH range of 5.0-6.9 and up to 35 °C. Both enzymes catalyzed 4 reactions, namely, intramolecular α-1,6-transglycosylation (cyclization), intermolecular α-1,6-transglycosylation, hydrolysis of CI4, and coupling reaction. Furthermore, the CI4-forming enzyme produced CI4 from α-1,6-linked glucan synthesized from starch by 6-α-glucosyltransferase. These findings will enable the production of CI4 from starch.

Fujita|Akihiro|A| Kawashima|Akira|A| Mitsukawa|Yuuki|Y| Kitagawa|Noriaki|N| Watanabe|Hikaru|H| Mori|Tetsuya|T| Nishimoto|Tomoyuki|T| Aga|Hajime|H| Ushio|Shimpei|S|

D006004:Glycogen Debranching Enzyme System

glucanotransferase
cycloisomaltooligosaccharide
cycloisomaltotetraose
transglycosylation
α-1,6 linkage


Matching of the postmortem hypothalamus from patients and controls.

Abstract: The quality of postmortem hypothalamus research depends strongly on a thorough clinical investigation and documentation of the patient's disorder and therapies. In addition, a systematic and professional neuropathological investigation of the entire brain of both the cases and the controls is absolutely crucial. In the experience of the Netherlands Brain Bank (NBB), about 20% of the clinical neurological diagnoses, despite being made in first rate clinics, have to be revised or require extra diagnoses after a complete and thorough neuropathologic review by the NBB. The neuropathology examination may reveal for instance that the elderly "controls" already have preclinical neurodegenerative alterations. In postmortem studies, the patient and control groups must be matched for as many as possible of the known confounding factors. This is necessary to make the groups as similar as possible, except for the topic being investigated. Confounding factors are present (i) before, (ii) during, and (iii) after death. They are, respectively: (i) genetic background, systemic diseases, duration and gravity of illness, medicines and addictive compounds used, age, sex, gender identity, sexual orientation, clock- and seasonal time of death, and lateralization; (ii) agonal state, stress of dying; and (iii) postmortem delay, freezing procedures, fixation, and storage time. Agonal state is generally estimated by measuring the pH of the brain. However, there are disorders in which pH is lower as a part of the disease process. Because of the large number of potentially confounding factors that differ according to, for instance, brain area and disease, a brain bank should have a large number of controls at its disposal for appropriate matching. If matching fails for some confounders, the influence of the confounders may be determined by statistical methods, such as analysis of variance or the regression models.

Postmortem hypothalamus
Controls
Neuropathologic review
Confounding factors
Age
Sex
Gender identity
Agonal state
Stress of dying
Postmortem delay
Clinical diagnosis and neuropathology


Biochemical responses to the toxicity of the biocide abamectin on the freshwater snail Physa acuta.

Abstract: The toxic effects of abamectin (ABM), an anthelmintic drug, on the snail, Physa Acuta, and the biochemical responses to the exposure stress were evaluated. The activities of superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), acetylcholinesterase (AChE), and nitric oxide synthase (NOS), and the contents of malondialdehyde (MDA) were determined in snail soft tissues (head, foot, visceral mass, and the mantle) for up to 96h of exposure to 3.4, 9.6, 19.2, or 27.4μgL(-1) of ABM. The results showed that SOD and GST activities were promoted by ABM-exposure at the earlier periods of treatment (12-48h) while these activites were inhibited at the end of test. The tendency of CAT activity was similar to that of SOD, but it increased at the end of test. MDA levels of the snail soft tissues increased in all treatment groups, including the recovery group, indicating that lipid peroxidation occurred in snail soft tissues. ABM-exposure inhibited AChE activity. However, NOS activities increased by ABM-exposure. In addition, activities of antioxidant enzymes and AChE from the snail soft tissues resumed the normal levels after 96h of recovery period, but MDA level did not attain the original level. This study provides information on the biochemical mechanism of ABM toxicity on the snail.

Ma|Junguo|J| Zhou|Chune|C| Li|Yao|Y| Li|Xiaoyu|X|

Abamectin
Physa acuta
Acetylcholinesterase
Nitric oxide synthase
Lipid peroxidation
Antioxidant enzymes


Near-ultraviolet-sensitive graphene/porous silicon photodetectors.

Abstract: Porous silicon (PSi) is recognized as an attractive building block for photonic devices because of its novel properties including high ratio of surface to volume and high light absorption. We first report near-ultraviolet (UV)-sensitive graphene/PSi photodetectors (PDs) fabricated by utilizing graphene and PSi as a carrier collector and a photoexcitation layer, respectively. Thanks to high light absorption and enlarged energy-band gap of PSi, the responsivity (Ri) and quantum efficiency (QE) of the PDs are markedly enhanced in the near-UV range. The performances of PDs are systemically studied for various porosities of PSi, controlled by varying the electroless-deposition time (td) of Ag nanoparticles for the use of Si etching. Largest gain is obtained at td = 3 s, consistent with the maximal enhancement of Ri and QE in the near UV range, which originates from the well-defined interface at the graphene/PSi junction, as proved by atomic- and electrostatic-force microscopies. Optimized response speed is ∼10 times faster compared to graphene/single-crystalline Si PDs. These and other unique PD characteristics prove to be governed by typical Schottky diode-like transport of charge carriers at the graphene/PSi junctions, based on bias-dependent variations of the band profiles, resulting in novel dark- and photocurrent behaviors.

Kim|Jungkil|J|
Joo|Soong Sin|SS|
Lee|Kyeong Won|KW|
Kim|Ju Hwan|JH|
Shin|Dong Hee|DH|
Kim|Sung|S|
Choi|Suk-Ho|SH|

graphene
photodetectors
near-ultraviolet
Schottky diode
porous Si


Methadone Reverses Analgesic Tolerance Induced by Morphine Pretreatment.

Abstract:
BACKGROUND
Opiates such as morphine are the most powerful analgesics, but their protracted use is restrained by the development of tolerance to analgesic effects. Recent works suggest that tolerance to morphine might be due to its inability to promote mu opioid receptor endocytosis, and the co-injection of morphine with a mu opioid receptor internalizing agonist like [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]enkephalin reduces tolerance to morphine. So far, no studies have been conducted to evaluate the ability of methadone to reduce morphine tolerance in morphine-pretreated animals, a treatment sequence that could be encountered in opiate rotation protocol. We investigated the ability of methadone (a mu opioid receptor internalizing agonist used in therapy) to reverse morphine tolerance and the associated cellular mechanisms in the periaqueductal gray matter, a region involved in pain control.

METHODS
We measured analgesic response following a challenge dose of morphine in the hot plate test and investigated regulation of mu opioid receptor (coupling and endocytosis) and some cellular mechanisms involved in tolerance such as adenylate cyclase superactivation and changes in N-methyl-d-aspartate receptor subunits expression and phosphorylation state.

RESULTS
A chronic treatment with morphine promoted tolerance to its analgesic effects and was associated with a lack of mu opioid receptor endocytosis, adenylate cyclase overshoot, NR2A and NR2B downregulation, and phosphorylation of NR1. We reported that a methadone treatment in morphine-treated mice reversed morphine tolerance to analgesia by promoting mu opioid receptor endocytosis and blocking cellular mechanisms of tolerance.

CONCLUSIONS
Our data might lead to rational strategies to tackle opiate tolerance in the frame of opiate rotation.

Posa|Luca|L| Accarie|Alison|A| Noble|Florence|F| Marie|Nicolas|N|

methadone
morphine
mu opioid receptor
endocytosis
adenylate cyclase
analgesia
NMDA receptor


Separation and purification of hemicellulose-derived saccharides from wood hydrolysate by combined process.

Abstract: Prehydrolysis of wood biomass prior to kraft cooking provides a stream containing hemicellulose-derived saccharides (HDSs) but also undesired non-saccharide compounds (NSCs) that were resulted from lignin depolymerization and carbohydrate degradation. In this study, a combined process consisting of lime treatment, resin adsorption, and gel filtration was developed to separate HDSs from NSCs. The macro-lignin impurities that accounted for 32.2% of NSCs were removed by lime treatment at 1.2% dosage with negligible HDSs loss. The majority of NSCs, lignin-derived phenolics, were eliminated by mixed bed ion exchange resin, elevating NSCs removal to 94.0%. The remaining NSCs, furfural and hydroxymethylfurfural, were excluded from HDSs by gel filtration. Chemical composition analysis showed that xylooligosaccharides (XOS) with the degree of depolymerization from 2 to 6 accounted for 28% of the total purified HDSs.

Wang|Xiaojun|X| Zhuang|Jingshun|J| Jiang|Jungang|J| Fu|Yingjuan|Y| Qin|Menghua|M| Wang|Zhaojiang|Z|

Purification Saccharide Lignin Hemicellulose Hydrolysis


Data, capacity-building, and training needs to address rural health inequities in the Northwest United States: a qualitative study.

Abstract:
OBJECTIVE
Rural public health system leaders struggle to access and use data for understanding local health inequities and to effectively allocate scarce resources to populations in need. This study sought to determine these rural public health system leaders' data access, capacity, and training needs.

MATERIALS AND METHODS
We conducted qualitative interviews across Alaska, Idaho, Oregon, and Washington with individuals expected to use population data for analysis or decision-making in rural communities. We used content analysis to identify themes.

RESULTS
We identified 2 broad themes: (1) challenges in accessing or using data to monitor and address health disparities and (2) needs for training in data use to address health inequities. Participants faced challenges accessing or using data to address rural disparities due to (a) limited availability or access to data, (b) data quality issues, (c) limited staff with expertise and resources for analyzing data, and (d) the diversity within rural jurisdictions. Participants also expressed opportunities for filling capacity gaps through training-particularly for displaying and communicating data.

DISCUSSION
Rural public health system leaders expressed data challenges, many of which can be aided by informatics solutions. These include interoperable, accessible, and usable tools that help capture, access, analyze, and display data to support health equity efforts in rural communities.

CONCLUSION
Informatics has the potential to address some of the daunting data-related challenges faced by rural public health system leaders working to enhance health equity. Future research should focus on developing informatics solutions to support data access and use in rural communities.

Bekemeier|Betty|B|
Park|Seungeun|S|
Backonja|Uba|U|
Ornelas|India|I|
Turner|Anne M|AM|

D000413:Alaska
D000068598:Data Accuracy
D003625:Data Collection
D054624:Health Status Disparities
D006801:Humans
D007407:Interviews as Topic
D015205:Northwestern United States
D040442:Public Health Informatics
D015980:Public Health Practice
D036301:Qualitative Research
D012423:Rural Health
D019035:Rural Health Services
D013192:Staff Development

rural health
public health
health equity
data accuracy
health impact assessment
public health informatics


A simple model of planar membrane: An integral equation investigation.

Abstract: A simple model of a lipid membrane, a binary mixture of saturated lipids and unsaturated lipids, was studied using an integral equation theory. The planar membrane is modeled as mixture of linear and bent molecules in two-dimensional space, and site-site radial distribution function, Kirkwood-Buff (KB) integral and related quantities were computed over the whole range of the molar fraction to understand their mixing behavior. We found that a close packing of linear molecules is enhanced as the fraction of bent molecules increases, but a long range correlation between the linear molecules is weakened. A high concentration of linear molecules promotes the demixing of linear molecules and bent molecules, and enhances the long range correlation between molecules. This implies that, the higher the concentration of linear molecules, the larger clusters tend to be formed. © 2018 Wiley Periodicals, Inc.


Exogenous indirect photoinactivation of bacterial pathogens and indicators in water with natural and synthetic photosensitizers in simulated sunlight with reduced UVB.

Abstract:
AIMS
To investigate the UVB-independent and exogenous indirect photoinactivation of eight human health-relevant bacterial species in the presence of photosensitizers.

METHODS AND RESULTS
Eight bacterial species were exposed to simulated sunlight with greatly reduced UVB light intensity in the presence of three synthetic photosensitizers and two natural photosensitizers. Inactivation curves were fit with shoulder log-linear or first-order kinetic models, from which the presence of a shoulder and magnitude of inactivation rate constants were compared. Eighty-four percent reduction in the UVB light intensity roughly matched a 72-95% reduction in the overall bacterial photoinactivation rate constants in sensitizer-free water. With the UVB light mostly reduced, the exogenous indirect mechanism contribution was evident for most bacteria and photosensitizers tested, although most prominently with the Gram-positive bacteria.

CONCLUSIONS
Results confirm the importance of UVB light in bacterial photoinactivation and, with the reduction of the UVB light intensity, that the Gram-positive bacteria are more vulnerable to the exogenous indirect mechanism than Gram-negative bacteria.

SIGNIFICANCE AND IMPACT OF THE STUDY
UVB is the most important range of the sunlight spectrum for bacterial photoinactivation. In aquatic environments where photosensitizers are present and there is high UVB light attenuation, UVA and visible wavelengths can contribute to exogenous indirect photoinactivation.

Maraccini|P A|PA|
Wenk|J|J|
Boehm|A B|AB|

exogenous
photoinactivation
pathogens
sunlight
UVB
bacteria
Escherichia coli
disinfection
enterococci
reactive oxygen species
sensitizers


Cardiac rehabilitation knowledge, awareness, and practice among cardiologists in India.

Abstract: Cardiac rehabilitation (CR) use is extremely low in India, and beyond. The reasons are multifactorial, including healthcare provider factors. This study examined CR perceptions among cardiologists in India. Attendees of the 2017 Cardiology Society of India conference completed a survey. Of 285 respondents, just over one-fourth had a CR program at their institution, with a similar proportion reporting someone dedicated to providing CR advice to their patients. Only 11 (3.9%) were correct in their responses to 4 multiple choice questions regarding secondary prevention. On average, cardiologists referred 20-30% of their patients, with the greatest barrier to referral being patient disinterest.

Ghisi|Gabriela Lima de Melo|GLM|
Contractor|Aashish|A|
Abhyankar|Mahesh|M|
Syed|Amrin|A|
Grace|Sherry L|SL|

D007722:Health Knowledge, Attitudes, Practice

Cardiac rehabilitation
Patient care management
Physicians’ practice patterns


Explainability for artificial intelligence in healthcare: a multidisciplinary perspective.

Abstract:
BACKGROUND
Explainability is one of the most heavily debated topics when it comes to the application of artificial intelligence (AI) in healthcare. Even though AI-driven systems have been shown to outperform humans in certain analytical tasks, the lack of explainability continues to spark criticism. Yet, explainability is not a purely technological issue, instead it invokes a host of medical, legal, ethical, and societal questions that require thorough exploration. This paper provides a comprehensive assessment of the role of explainability in medical AI and makes an ethical evaluation of what explainability means for the adoption of AI-driven tools into clinical practice.

METHODS
Taking AI-based clinical decision support systems as a case in point, we adopted a multidisciplinary approach to analyze the relevance of explainability for medical AI from the technological, legal, medical, and patient perspectives. Drawing on the findings of this conceptual analysis, we then conducted an ethical assessment using the "Principles of Biomedical Ethics" by Beauchamp and Childress (autonomy, beneficence, nonmaleficence, and justice) as an analytical framework to determine the need for explainability in medical AI.

RESULTS
Each of the domains highlights a different set of core considerations and values that are relevant for understanding the role of explainability in clinical practice. From the technological point of view, explainability has to be considered both in terms how it can be achieved and what is beneficial from a development perspective. When looking at the legal perspective we identified informed consent, certification and approval as medical devices, and liability as core touchpoints for explainability. Both the medical and patient perspectives emphasize the importance of considering the interplay between human actors and medical AI. We conclude that omitting explainability in clinical decision support systems poses a threat to core ethical values in medicine and may have detrimental consequences for individual and public health.

CONCLUSIONS
To ensure that medical AI lives up to its promises, there is a need to sensitize developers, healthcare professionals, and legislators to the challenges and limitations of opaque algorithms in medical AI and to foster multidisciplinary collaboration moving forward.

Amann|Julia|J|0000-0003-2155-5286
Blasimme|Alessandro|A|
Vayena|Effy|E|
Frey|Dietmar|D|
Madai|Vince I|VI|
|||

D020000:Decision Support Systems, Clinical

Explainability
Artificial intelligence
Clinical decision support
Interpretability
Machine learning


Roles of Runx2 in Skeletal Development.

Abstract: Runx2 is the most upstream transcription factor essential for osteoblast differentiation. It regulates the expression of Sp7, the protein of which is a crucial transcription factor for osteoblast differentiation, as well as that of bone matrix genes including Spp1, Ibsp, and Bglap2. Runx2 is also required for chondrocyte maturation, and Runx3 has a redundant function with Runx2 in chondrocyte maturation. Runx2 regulates the expression of Col10a1, Spp1, Ibsp, and Mmp13 in chondrocytes. It also inhibits chondrocytes from acquiring the phenotypes of permanent cartilage chondrocytes. It regulates chondrocyte proliferation through the regulation of Ihh expression. Runx2 enhances osteoclastogenesis by regulating Rankl. Cbfb, which is a co-transcription factor for Runx family proteins, plays an important role in skeletal development by stabilizing Runx family proteins. In Cbfb isoforms, Cbfb1 is more potent than Cbfb2 in Runx2-dependent transcriptional regulation; however, the expression level of Cbfb2 is three-fold higher than that of Cbfb1, demonstrating the requirement of Cbfb2 in skeletal development. The expression of Runx2 in osteoblasts is regulated by a 343-bp enhancer located upstream of the P1 promoter. This enhancer is activated by an enhanceosome composed of Dlx5/6, Mef2, Tcf7, Ctnnb1, Sox5/6, Smad1, and Sp7. Thus, Runx2 is a multifunctional transcription factor that is essential for skeletal development, and Cbfb regulates skeletal development by modulating the stability and transcriptional activity of Runx family proteins.

D050659:Core Binding Factor Alpha 1 Subunit

Runx2 Osteoblast Chondrocyte Enhancer Cbfb


Pictorial review of tips and tricks for ureteroscopy and stone treatment: an essential guide for urologists from PETRA research consortium.

Abstract: With an increase in the number of ureteroscopy (URS) procedures, URS is now performed more widely and is becoming a standard procedure for all urologists. There is also a rise in the complexity of these procedures and URS is now offered for treatment of stones as well as for diagnosis and treatment of urothelial tumours. We wanted to provide a 'pictorial review' of the 'tips and tricks' of URS, as the finer and technical details are often easier to understand and remember with images rather than through textual explanations.

Somani|Bhaskar K|BK|
Ploumidis|Achilles|A|
Pappas|Athanasios|A|
Doizi|Steeve|S|
Babawale|Omikunle|O|
Dragos|Laurian|L|
Sener|Emre|E|
Talso|Michele|M|
Tefik|Tzevat|T|
Kronenberg|Peter|P|
Emiliani|Esteban|E|
Villa|Luca|L|
Kamphuis|Guido|G|
Proietti|Silvia|S|
Traxer|Olivier|O|

tips and tricks
stones
Ureteroscopy (URS)
RIRS
urolithiasis


Identification of novel genetic causes of Rett syndrome-like phenotypes.

Abstract:
BACKGROUND
The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach.

METHODS AND RESULTS
We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT.

CONCLUSIONS
Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes.

Lopes|Fátima|F|
Barbosa|Mafalda|M|
Ameur|Adam|A|
Soares|Gabriela|G|
de Sá|Joaquim|J|
Dias|Ana Isabel|AI|
Oliveira|Guiomar|G|
Cabral|Pedro|P|
Temudo|Teresa|T|
Calado|Eulália|E|
Cruz|Isabel Fineza|IF|
Vieira|José Pedro|JP|
Oliveira|Renata|R|
Esteves|Sofia|S|
Sauer|Sascha|S|
Jonasson|Inger|I|
Syvänen|Ann-Christine|AC|
Gyllensten|Ulf|U|
Pinto|Dalila|D|
Maciel|Patrícia|P|

Whole exome sequencing
Rett syndrome
Epilepsy
Intellectual disability


Population Genetics of Fusarium graminearum at the Interface of Wheat and Wild Grass Communities in New York.

Abstract: Fusarium graminearum is primarily understood as an agricultural pathogen affecting cereal crops, but its host range also includes diverse, noncultivated grasses ubiquitous across agricultural and natural environments. Wild grasses may select for the production of diverse toxin variants (chemotypes) and serve as reservoirs of genetic diversity or sources of disease-inciting inoculum. Populations at the intersection of wheat and wild grass communities were described using 909 isolates collected from wheat spikes, wild grass spikes, and overwintered wild grass stems found at natural and agricultural sites in regions of high and low crop production. Trichothecene (TRI) genotypes correlated to pathogen chemotype were predicted from two loci, and multilocus genotypes (MLGs) were determined using eight microsatellite loci. The genetic diversity of wild grass and wheat-derived populations was comparable, and their differentiation was low. Duplicate MLGs were rare even in samples collected from a single square meter, although they could be found in multiple hosts, environments, regions, and years. TRI genotype frequencies differed between region and land use. Admixture between TRI genotype-defined populations, which correspond to three previously described sympatric North American populations, was detected and was highest in a region with remote host communities and little agricultural production. Nonagricultural environments may maintain different pathogen TRI genotypes than wheat fields and provide an opportunity for recombination between isolates from different F. graminearum populations. A lack of structural barriers suggests that pathogen gene flow is uninhibited between wheat and wild grass communities, and the recovery of putative clones from multiple hosts and environments provides initial evidence that noncultivated grasses are a source of local and regional inoculum.

Fusarium graminearum
grasses
ecology and epidemiology
mycology
population biology
wild hosts


Low interatrial septal pacing: A simple method.

Abstract:
BACKGROUND
Sinus node disease is associated with widespread structural and electrophysiological changes in the atria in addition to abnormalities at the sinus node. The atrial conduction disorder in patients with atrial pacing results in higher incidence of atrial fibrillation. Studies have shown that low interatrial septal pacing is superior to right atrial appendage pacing in preventing persistent or permanent atrial fibrillation in these patients. However, implantation of active fixation lead in low interatrial septal position is difficult and time consuming with conventional stylet, inhibiting application of this method in routine practice.

METHOD
The technique of implanting atrial pacing lead in low interatrial septum with hand-made stylet is presented in this study with emphasis on fluoroscopic landmark and electrocardiographic P wave pattern.

RESULTS
The results indicate acute and short-term success of low interatrial septal pacing in 10 patients out of 11 patients without major complications. Pacing parameters during implantation and 3 months post procedure were within normal limits.

CONCLUSION
The initial favorable results of this study indicate low interatrial septal pacing with conventional active fixation lead using fluoroscopic landmark and electrocardiographic characteristics is feasible and reproducible with a simple technique.

Pacing
Interatrial septum
Coronary sinus


Evaluating the potential of deep brain stimulation for treatment-resistant anorexia nervosa.

Abstract: Anorexia nervosa is a chronic and debilitating psychiatric disorder associated with one of the highest mortality rates of any psychiatric condition. Despite advances in neuroimaging, genetics, pharmacology, and psychosocial interventions in the last half-century, little progress has been made in altering the natural history of the condition or its outcomes. Evidence is now emerging that the condition is, at least in part, maintained by dysfunctional activity in key neuroanatomic circuits subserving illness-maintaining symptoms. Abnormal reward processing, compulsive hyperactivity, chronic anxiety, and depression, all suggest that anorexia nervosa shares much in common with other conditions, such as major depression and obsessive-compulsive disorder, for which surgical therapy with deep brain stimulation (DBS) has been tried, with promising results. As a result, the use of DBS in treatment-resistant anorexia nervosa should be evaluated in carefully designed, early-phase feasibility trials.

Lipsman|Nir|N|
Woodside|Blake|B|
Lozano|Andres M|AM|

D000856:Anorexia Nervosa
D046690:Deep Brain Stimulation
D005069:Evaluation Studies as Topic
D006801:Humans

deep brain stimulation
anorexia nervosa
depression
anterior cingulate
insular cortex
interoception
nucleus accumbens


Using School Climate to Improve Attendance and Grades: Understanding the Importance of School Satisfaction Among Middle and High School Students.

Abstract:
BACKGROUND
Students with chronic absences tend to struggle academically and may not benefit fully from all school has to offer. A positive school climate has been shown to reduce absenteeism and promote academic success. In this study, we explored how a positive school climate and high satisfaction with school may influence absences and academic performance.

METHODS
We used mediated path analysis to describe relationships involving school climate, school satisfaction, absences, and grades among 6839 middle school (49% female, 82% white) and 7470 high school (51% female, 85.0% white) students from 26 West Virginia schools.

RESULTS
In the middle and high school samples, we found that a positive school climate and high satisfaction with school reduces school absenteeism. Findings also suggest students with more absences tend to perform less well academically; a positive school climate and school satisfaction may promote good grades.

CONCLUSIONS
Missing a substantial amount of school days for any reason may hinder students academic success, but "skipping" may require added attention. Improving school climate and student satisfaction with school may contribute to better attendance and grades.

Daily|Shay M|SM|0000-0003-0455-6762
Smith|Megan L|ML|
Lilly|Christa L|CL|
Davidov|Danielle M|DM|
Mann|Michael J|MJ|
Kristjansson|Alfgeir L|AL|

school absenteeism
adolescence
adolescents
mediation analysis
school contentment
truancy


Carbohydrate-Processing Enzymes of the Lysosome: Diseases Caused by Misfolded Mutants and Sugar Mimetics as Correcting Pharmacological Chaperones.

Abstract: Lysosomal storage diseases are hereditary disorders caused by mutations on genes encoding for one of the more than fifty lysosomal enzymes involved in the highly ordered degradation cascades of glycans, glycoconjugates, and other complex biomolecules in the lysosome. Several of these metabolic disorders are associated with the absence or the lack of activity of carbohydrate-processing enzymes in this cell compartment. In a recently introduced therapy concept, for susceptible mutants, small substrate-related molecules (so-called pharmacological chaperones), such as reversible inhibitors of these enzymes, may serve as templates for the correct folding and transport of the respective protein mutant, thus improving its concentration and, consequently, its enzymatic activity in the lysosome. Carbohydrate-processing enzymes in the lysosome, related lysosomal diseases, and the scope and limitations of reported reversible inhibitors as pharmacological chaperones are discussed with a view to possibly extending and improving research efforts in this area of orphan diseases.


Does the addition of two exercise-focussed home visits to usual care improve outcomes for patients with balance impairments? A randomized controlled trial.

Abstract:
OBJECTIVE
To investigate whether two additional home visits improve outcomes for rehabilitation outpatients with balance impairments compared to usual care.

DESIGN
Randomized controlled trial.

SETTING
Outpatient rehabilitation.

PARTICIPANTS
Fifty with balance impairments.

INTERVENTIONS
Both groups received usual care including weekly group exercise over eight weeks. The intervention group received two home visits to individualize home exercises.

OUTCOME MEASURES
Primary outcome measure was the Balance Outcome Measure for Elder Rehabilitation (BOOMER) score, and secondary outcomes included force platform measures using the NeuroCom Balance Master®, assessed at baseline, after intervention and three-month follow-up.

RESULTS
There was no between-group difference for BOOMER score. There were significant between-group differences in favour of the intervention group for limits of stability reaction time at week 9 (mean difference (MD) -0.27, 95% confidence interval (CI) -0.44 to -0.09) and week 22 (MD -0.28, 95% CI -0.45 to -0.10) and for limits of stability maximal excursion at week 9 (MD 8.66, 95% CI 1.67 to 15.65) and week 22 (MD 14.58, 95% CI 7.59 to 21.57). Significant between-group differences favoured the control group for Clinical Test of Sensory Interaction of Balance at week 9 (MD 0.40, 95% CI 0.13 to 0.66) and week 22 (MD 0.45, 95% CI 0.18 to 0.72) and step quick turn time at week 9 (MD 0.56, 95% CI 0.02 to 1.10).

CONCLUSION
Two exercise-focussed home visits improved some dynamic balance outcomes in older patients with balance impairments. Some outcomes showed significant improvements with small effect sizes in favour of the control group which may be chance findings or because they completed a standard home exercise programme.

Whitbourne|Craig|C|
Shields|Nora|N|
Tacey|Mark|M|
Koh|Kenneth Wz|KW|
Lawler|Katherine|K|
Hill|Keith D|KD|

Home visits
balance
rehabilitation interventions


Decreased plasma levels of brain-derived neurotrophic factor (BDNF) during mixed episodes of bipolar disorder.

Abstract:
BACKGROUND
Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neurogenesis and neuroplasticity. Decreased blood levels of BDNF have been found during acute manic and depressive states. BDNF has been proposed as a biomarker in illness phases of mood disorders. No information is available regarding BDNF levels during the mixed states of bipolar disorder (BD). The aim of this study was to evaluate BDNF levels during mixed episodes of BD patients and compare them with those of healthy subjects and depressed patients.

METHODS
Plasma BDNF levels were measured by an ELISA assay in 18 patients with major depressive episode (MDE), 19 patients with mixed episode (ME) and 15 healthy subjects (HS).

RESULTS
BDNF levels were significantly higher in HS, as compared with patients׳ samples (HS vs. MDE patients: p<001; HS vs. ME patients: p=.022). No significant differences were found between BDNF levels of ME and MDE patients. The severity of illness as assessed by CGI-S was significantly higher in ME than in MDE patients (p=.01).

LIMITATIONS
The small sample size may have weakened the power of statistical analyses. All patients received mood-stabilizing and antidepressant treatments which have been reported to influence peripheral BDNF levels.

CONCLUSIONS
Our results are consistent with previous studies showing reduced BDNF during both manic and depressive episodes. This finding supports the role of BDNF as a state-marker of mood episodes, and may represent a contribution to a unitary approach model between unipolar and BDs, as well as to the manic-depressive spectrum model.

Piccinni|Armando|A|
Veltri|Antonello|A|
Costanzo|Davide|D|
Vanelli|Federica|F|
Franceschini|Caterina|C|
Moroni|Ilenia|I|
Domenici|Luciano|L|
Origlia|Nicola|N|
Marazziti|Donatella|D|
Akiskal|Hagop Souren|HS|
Dell'Osso|Liliana|L|

BDNF
Bipolar disorder
Biomarkers
Mixed state
Bipolar spectrum
DSM-5


Molecular characterization of phytoplasmas of 'Clover proliferation' group associated with three ornamental plant species in India.

Abstract: Suspected phytoplasma symptoms of little leaf, yellowing, chlorosis, phyllody, witches' broom, and stunting were observed on ten different ornamental plant species at New Delhi, Andhra Pradesh, Haryana, Bengaluru, and Pune, India, during March to July 2016. To investigate the possibility of phytoplasma etiology, PCR assays were performed using universal primer pairs (P1/P7 followed by 3Far/3Rev) specific to the phytoplasma 16Sr RNA gene. First round PCR amplification with primer pair P1/P7 did not yield expected 1.8 kb product of 16S rRNA region from any of the 17 symptomatic samples. However, 1.3 Kb amplicons were observed in nested PCR assays with 3Far/3Rev primer pair in symptomatic leaf samples of Hibiscus rosa-sinensis L. (Pune isolate), Saponaria officinalis L. (Pune isolate), and Allamanda cathartica L. (Delhi isolate). No amplifications were observed in any of the other tested symptomatic and non-symptomatic plant samples either in first round or second round of nested PCR assays with phytoplasma specific primer pairs. Pairwise sequence comparison of 16S rDNA sequences of the five positive phytoplasma strains of A. catharica, H. rosa-sinensis, and S. officinalis in the present study revealed 99-100% sequence identities with strains of 'clover proliferation' (16SrVI) group. Phylogenetic and virtual RFLP analysis of 16S rDNA sequences of the five identified phytoplasma strains belonging to three ornamental species further confirmed their clustering and grouping with member strains of 'clover proliferation' subgroup D. This is the first record of the phytoplasma association of 'clover proliferation' subgroup D with H. rosa-sinensis, S. officinalis, and A. cathartica in the world.

Khasa|Ekta|E|
Gopala|||
Taloh|Aido|A|
Prabha|T|T|
Madhupriya|||
Rao|G P|GP|

Phytoplasma
India
Hibiscus rosa-sinensis L.
Saponaria officinalis L.
Allamanda cathartica L.
16Sr VI-D subgroup
Identification


The Evolving Hospital Market in China After the 2009 Healthcare Reform.

Abstract: Since the initiation of national healthcare reform in 2009, China's hospital market has witnessed significant change. To provide a brief description about its evolving process, China Health Statistical Yearbook data and Sichuan administrative data from 2009 to 2017 were used in this article. An overall upward trend of hospital delivery capacity was found in this study, which increased from 3.12 million beds and 1.09 million doctors in 2009 to 6.12 million and 1.80 million in 2017, respectively, while the primary healthcare institutions presented fairly slow development pace. Growing proportion of medical resources and patients gathered in hospitals, especially tertiary hospitals. While private hospitals demonstrated an increasingly important role in hospital market with growing share of capacity and service, their average capacity, especially the human resource, was found to be much lower than that of public hospitals and the gaps are still widening. The competition among hospitals grouped by homogeneous ownership types has predominated the increasingly intensified hospital market competition in China. In order to adapt to the raising demand of health care in China, it is highly recommended that strategies forged at governmental levels be focused on primary care promotion, guiding the development of private hospitals as well as on promoting orderly competition in the hospital market.

China
capacity
hospital competition
market share
medical service


Healthcare Costs Incurred by Patients with Multiple Myeloma Following Triple Class Exposure (TCE) in the US.

Abstract:
INTRODUCTION
Multiple myeloma (MM) is a malignancy of plasma cells; most MM patients will eventually relapse or become refractory to treatment. Treating MM patients remains a challenge since patients eventually progress through several lines of therapy (LOTs), requiring the use of multiple MM drug classes. We examined healthcare resource utilization (HCRU) and the costs incurred by MM patients following triple class exposure (TCE; defined as exposure to a proteosome inhibitor, an immunomodulatory agent, and an anti-CD-38 antibody).

METHODS
Adult MM patients were selected from the MarketScan® commercial and Medicare supplemental databases (January 2009-February 2021). From this cohort, patients who had TCE and ≥ 1 subsequent LOT that occurred after January 1, 2017 were included in the study population. The initiation date for the first post-TCE LOT was defined as the index date. All-cause and MM-related HCRU and the associated costs were examined post-index date.

RESULTS
A total of 85 MM patients with TCE who initiated ≥ 1 subsequent LOT post-TCE and had ≥ 1 year of follow-up post-index date were included in the study population; mean age on index date was 58.8 years, and 60.0% were male. The time from first-observed MM diagnosis until index date averaged 47.5 months. During an average follow-up of 20.9 months post-index date, 64.7% of patients (N = 55) initiated a second LOT and 35.2% (N = 30) received at least 3 LOTs. During follow-up, mean total all-cause healthcare cost per patient was $722,992 (equivalent to $34,578 per patient per month [PPPM]). Approximately 90.7% ($655,524 per patient) of the total all-cause healthcare costs were MM related, 66.0% of which were MM drug/infusion costs.

CONCLUSION
In this real-world US study, MM patients with TCE incurred high healthcare costs, with the majority being MM related and primarily attributed to MM drug and infusion costs.

Jagannath|Sundar|S|
Joseph|Nedra|N|
He|Jinghua|J|
Crivera|Concetta|C|
Fu|Alex Z|AZ|
Garret|Ashraf|A|
Shah|Nina|N|

Healthcare costs
Multiple myeloma
Triple class exposure
Healthcare resource utilization


From Northern Ireland to Afghanistan: half a century of blast injuries.

Abstract:
INTRODUCTION
Throughout the last half century, blast injuries have been a common occurrence to UK military personnel during combat operations. This study investigates casualty data from three different military operations to determine whether survivability from blast injuries has improved over time and whether the tactics used could have influenced the injuries sustained.

METHODS
Casualty data from operations in Northern Ireland, Iraq and Afghanistan were reviewed and found to contain a total of 2629 casualties injured by improvised explosive devices. The injury severities were examined and the suitability of comparison between conflicts was considered.

RESULTS
The case fatality rate and mean severity score sustained remained consistent among the operations included in this study. Using the New Injury Severity Score, the probabilities of survival were calculated for each separate operation. The body regions injured were identified for both fatalities and survivors. Using this information, comparisons of injury severities sustained at an Abbreviated Injury Scale of 3 and above (identified as a threshold for fatal injury) were conducted between the different operations.

CONCLUSIONS
The data showed that as operations changed over time, survivability improved and the proportions of body regions injured also changed; however, this study also highlights how studying casualty data from different conflicts without taking account for the contextual differences may lead to misleading conclusions.


Angiogenic Properties of Concentrated Growth Factors (CGFs): The Role of Soluble Factors and Cellular Components.

Abstract: Blood-derived concentrated growth factors (CGFs) represent a novel autologous biomaterial with promising applications in regenerative medicine. Angiogenesis is a key factor in tissue regeneration, but the role played by CGFs in vessel formation is not clear. The purpose of this study was to characterize the angiogenic properties of CGFs by evaluating the effects of its soluble factors and cellular components on the neovascularization in an in vitro model of angiogenesis. CGF clots were cultured for 14 days in cell culture medium; after that, CGF-conditioned medium (CGF-CM) was collected, and soluble factors and cellular components were separated and characterized. CGF-soluble factors, such as growth factors (VEGF and TGF-β1) and matrix metalloproteinases (MMP-2 and -9), were assessed by ELISA. Angiogenic properties of CGF-soluble factors were analyzed by stimulating human cultured endothelial cells with increasing concentrations (1%, 5%, 10%, or 20%) of CGF-CM, and their effect on cell migration and tubule-like formation was assessed by wound healing and Matrigel assay, respectively. The expression of endothelial angiogenic mediators was determined using qRT-PCR and ELISA assays. CGF-derived cells were characterized by immunostaining, qRT-PCR and Matrigel assay. We found that CGF-CM, consisting of essential pro-angiogenic factors, such as VEGF, TGF-β1, MMP-9, and MMP-2, promoted endothelial cell migration; tubule structure formation; and endothelial expression of multiple angiogenic mediators, including growth factors, chemokines, and metalloproteinases. Moreover, we discovered that CGF-derived cells exhibited features such as endothelial progenitor cells, since they expressed the CD34 stem cell marker and endothelial markers and participated in the neo-angiogenic process. In conclusion, our results suggest that CGFs are able to promote endothelial angiogenesis through their soluble and cellular components and that CGFs can be used as a biomaterial for therapeutic vasculogenesis in the field of tissue regeneration.

concentrated growth factors (CGFs)
biomaterials
angiogenesis
tissue regeneration
matrix metalloproteinases
endothelial cells
pro-angiogenic factors
endothelial markers
vasculogenesis
endothelial progenitor cells (EPCs)


Biomechanical optimization of the angle and position for surgical implantation of a straight short stem hip implant.

Abstract: Conservative hip implants preserve healthy bone for revision surgeries and improve physiological loading; however, they have little supporting biomechanical data with respect to their 3D orientation during implantation. This study endeavored to determine the optimal 3D orientation of a straight short stem hip implant within the proximal femur that would yield a stress distribution most similar to an intact femur. Synthetic femurs were implanted with a stem in one of seven maximum angles or positions and axially loaded, with resultant strain values used to validate a finite element model. Design of experiments was used to analyze the range of potential implant orientations under three gait cycle loading conditions. A global optimal orientation of 9.14° valgus, 2.49° anteversion, 0.48mm posterior position, and 0.23mm inferior position was found to yield stress distributions most similar to the intact femur across the gait cycle range. In general, it was determined that the valgus orientation was optimal throughout the gait cycle, consistently exhibiting a stress distribution more similar to that of the intact femur. Minimal levels of anterior/posterior and inferior positioning were seen to be beneficial in achieving more physiological stresses in specific regions of interest within the proximal femur, while the anteverted orientation was only beneficial in loading under flexion. Overall, orthopaedic surgeons should aim to implant straight short stem hip implants in valgus up to 10°, with an otherwise neutral position and version, unless some degree of deviation would be beneficial for a patient-specific reason. This work has implications for the best surgical placement of straight short stem hip implants to yield maximal biomechanical stability.

Cook|Gillian E|GE|
Samiezadeh|Saeid|S|
Morison|Zachary|Z|
Aziz|Mina S R|MS|
Bougherara|Habiba|H|
Zdero|Radovan|R|
Schemitsch|Emil H|EH|

D001696:Biomechanical Phenomena
D005269:Femur
D020342:Finite Element Analysis
D006622:Hip Prosthesis
D006801:Humans
D055595:Mechanical Phenomena
D013314:Stress, Mechanical

Biomechanics
Stress
Finite element analysis
Hip arthroplasty
Short-stem


Association between computed tomography-derived tricuspid annular dimensions and prognosis: insights from whole-beat computed tomography assessment.

Abstract:
AIMS
Tricuspid regurgitation (TR) has been associated with outcome in patients treated with transcatheter aortic valve implantation (TAVI). Tricuspid annulus (TA) dimensions are associated with TR. However, the TA is highly dynamic during the cardiac cycle, and the interaction between the TA dimensions, TR, and patient prognosis has never been evaluated. This study aimed to characterize the dynamics of the TA along with the cardiac cycle and its association with prognosis in patients undergoing TAVI.

METHODS AND RESULTS
Patients with severe aortic stenosis who underwent whole-beat computed tomography (n = 393, mean age 80 ± 7 years, 53% male) were included. The ratio between anterior-posterior (AP) and septal-lateral (SL) diameter of the TA was calculated at end-systole (ES), mid-diastole (MD), and end-diastole (ED) to characterize the TA shape throughout the cardiac cycle. The primary endpoint was all-cause mortality. During a median 3.6 (1.7-5.5) years of follow-up, 146 patients died. While all the TA parameters at ES and MD were not associated with all-cause mortality, a low AP/SL ratio at ED (more circular geometry) was independently related with all-cause mortality (hazard ratio: 4.717, 95% confidence interval: 1.481-15.152; P = 0.009). In addition, a more circular TA shape at ED (AP/SL ratio < 1.20) was also associated with more right atrial and ventricular dilation, more significant TR, and a higher prevalence of atrial fibrillation.

CONCLUSION
Circular remodelling of the TA shape at ED is associated with more right atrial and ventricular dilation, and a higher long-term mortality after TAVI. The evaluation of the TA shape at ED may be a useful parameter in the risk stratification of patients undergoing TAVI.

computed tomography
transcatheter aortic valve implantation
tricuspid valve


Plant phosphoinositide signaling - dynamics on demand.

Abstract: Eukaryotic membranes contain small amounts of lipids with regulatory roles. An important class of such regulatory lipids are phosphoinositides (PIs). Within membranes, PIs serve as recruitment signals, as regulators of membrane protein function or as precursors for second messenger production, thereby influencing a multitude of cellular processes with key importance for plant function and development. Plant PIs occur locally and transiently within membrane microdomains, and their abundance is strictly controlled. To understand the functions of the plant PI-network it is important to understand not only downstream PI-effects, but also to identify and characterize factors contributing to dynamic PI formation. This article is part of a Special Issue entitled: Plant Lipid Biology edited by Kent D. Chapman and Ivo Feussner.

Plant phosphoinositides
Dynamics
Membrane association
PI-kinases
Posttranslational modification


Biomarkers of Presbycusis and Tinnitus in a Portuguese Older Population.

Abstract: Introduction: Presbycusis or age-related hearing loss (ARHL) is a ubiquitous health problem. It is estimated that it will affect up to 1.5 billion people by 2025. In addition, tinnitus occurs in a large majority of cases with presbycusis. Glutamate metabotropic receptor 7 (GRM7) and N-acetyltransferase 2 (NAT2) are some of the genetic markers for presbycusis. Objectives: To explore patterns of hearing loss and the role of GRM7 and NAT2 as possible markers of presbycusis and tinnitus in a Portuguese population sample. Materials and Methods: Tonal and speech audiometry, tinnitus assessment, clinical interview, and DNA samples were obtained from patients aged from 55 to 75 with or without tinnitus. GRM7 analysis was performed by qPCR. Genotyping of single nucleotide polymorphisms (SNPs) in NAT2 was performed by PCR amplification followed by Sanger sequencing or by qPCR. Results: We screened samples from 78 individuals (33 men and 45 women). T allele at GRM7 gene was the most observed (60.3% T/T and 33.3% A/T). Individuals with a T/T genotype have a higher risk for ARHL and 33% lower risk for tinnitus, compared to individuals with A/A and A/T genotype, respectively. Being a slow acetylator (53%) was the most common NAT2 phenotype, more common in men (55.8%). Intermediate acetylator was the second most common phenotype (35.9%) also more frequent in men (82.6%). Noise exposed individuals and individuals with 'high frequency' hearing loss seem to have a higher risk for tinnitus. Our data suggests that allele AT of GRM7 can have a statistically significant influence toward the severity of tinnitus. Conclusion: For each increasing year of age the chance of HL increases by 9%. The risk for ARHL was not significantly associated with GRM7 neither NAT2. However, we cannot conclude from our data whether the presence of T allele at GRM7 increases the odds for ARHL or whether the A allele has a protective effect. Genotype A/T at GRM7 could potentially be considered a biomarker of tinnitus severity. This is the first study evaluating the effect of GRM7 and NAT2 gene in tinnitus.

Haider|Haúla F|HF|
Flook|Marisa|M|
Aparicio|Mariana|M|
Ribeiro|Diogo|D|
Antunes|Marilia|M|
Szczepek|Agnieszka J|AJ|
Hoare|Derek J|DJ|
Fialho|Graça|G|
Paço|João C|JC|
Caria|Helena|H|

presbycusis tinnitus GRM7 NAT2 markers comorbidities


Differentiation between nasopharyngeal carcinoma and lymphoma at the primary site using whole-tumor histogram analysis of apparent diffusion coefficient maps.

Abstract:
INTRODUCTION
To determine the value of whole-tumor histogram analysis of apparent diffusion coefficient (ADC) maps in differentiating nasopharyngeal carcinoma (NPC) from lymphoma (NPL) at the primary site METHOD AND MATERIALS: One hundred forty-seven patients with nasopharyngeal tumors (89 NPCs and 38 NPLs) who had undergone magnetic resonance imaging (MRI) and diffusion-weighted imaging were retrospectively analyzed. ADC histogram-derived parameters were compared between the NPC and NPL groups by using the Mann-Whitney U test. Receiver operating characteristic (ROC) curves of the histogram parameters were plotted for diagnostic accuracy. Sensitivity and specificity were calculated for each histogram parameter.

RESULTS
In whole-tumor histogram analysis, the mean, median, and 10th and 25th percentiles of ADC were all significantly higher in NPC than NPL (P = 0.045, P = 0.035, P = 0.005, and P = 0.016, respectively). Uniformity was significantly higher in NPC than NPL (P = 0.001). Skewness was significantly lower in NPC than NPL (P = 0.039). For the conventional ROI-based method, ADCmean values were significantly higher in NPC than in NPL (P = 0.009). The ROC curve analysis showed that uniformity yielded the largest area under the curve (AUC = 0.768) for differentiating NPC from NPL among all ADC metrics, followed by 10th percentiles of ADC (AUC = 0.725); sensitivity and specificity were 76.5% and 71.4%, respectively.

CONCLUSION
Whole-tumor histogram analysis of ADC maps could be helpful for differentiating NPC from NPL.

Lian|Shanshan|S| Zhang|Cheng|C| Chi|Jun|J| Huang|Yingyi|Y| Shi|Feng|F| Xie|Chuanmiao|C|

D038524:Diffusion Magnetic Resonance Imaging

Nasopharyngeal carcinoma
Lymphoma
Histogram analysis
MRI
DWI


Radiological Evaluation of Juvenile osteochondral Conditions in Brazilian Warmblood Horse.

Abstract: The term juvenile osteochondral condition (JOCC) has been used to identify developmental changes in the growth plates. The condition is characterized by a set of changes with similar pathogenesis that affect the immature skeleton and joints of growing foals. The aim of the current study is to investigate the prevalence and degree of severity of osteochondral changes in Brazilian warmblood (BW) foals in two farms in the south of Brazil. Radiological evaluation was applied to the metacarpophalangeal (MCP), carpal (C), metatarsophalangeal (MTP), tarsal (T), and femorotibiopatellar (FTP) joints of 90 foals (47 females and 43 males) in the age group 16-36 months. The evaluation was made before the animals started their athlete performance. Changes were classified as a degree of severity 0 to 4. Changes were diagnosed in 56 foals (58%) that had 105 affected joints. Thirty-three (59%) out of the 56 animals had changes in more than one joint; 57% (19/33) of them had bilateral changes. MTP and MCP were the joints with the most severe changes, respectively (severity 2 and 3), followed by FTP, T, and C. Osteochondral fragments (59%), tarsal arthropathies (48%), irregularities and radiolucency in the FTP joint (7%), and subchondral cystic lesion in the FTP joint (1%), were the most observed changes. BW foals recorded the high prevalence of osteochondral alterations; although MTP and T were the most affected joints, MTP and MCP presented the most severe changes. The present study confirmed significant JOCC prevalence in BW. Further studies should be carried out in different properties.

Gonçalves|Lessana M|LM|
Pozzobon|Ricardo|R|
Dos Anjos|Bruno L|BL|
Pellegrini|Débora C P|DCP|
Azevedo|Marcos S|MS|
Dau|Stefano L|SL|
Oliveira|Guilherme P|GP|
Klaus|Rosana|R|

Endochondral ossification
Orthopedic disease
Osteoarticular changes


Contribution of IL-1β, 6 and TNF-α to the form of post-traumatic osteoarthritis induced by "idealized" anterior cruciate ligament reconstruction in a porcine model.

Abstract:
BACKGROUND
It has been noted that anterior cruciate ligament (ACL) injury-induced cartilage degeneration is the key risk factor for post-traumatic osteoarthritis (PTOA). However, whether the cartilage degeneration after ACL injury is caused by inflammation, abnormal biomechanics or both remains largely unknown, as there has been no animal model for separating the two factors so far.

METHODS
Eighteen-month-old female mini-pigs were divided into an "idealized" anterior cruciate ligament reconstruction (IACLR) group and a control group (n = 16 limbs per group). Real-time PCR, safranine O staining and indian ink staining were performed to verify whether animal models were successfully established or not. Multiple linear regression analysis was used to evaluate the correlation between levels of the inflammatory factors (including interferon [IFN]-γ, interleukin [IL]-1β, IL-4, IL-6, IL-8, IL-10, IL-12 and tumor necrosis factor [TNF]-α measured by the Luminex method) and changes in cartilage histology (quantified by morphological scoring) after surgery.

RESULTS
A significant OA cartilage damage with increased MMP-1, MMP-13 mRNA levels and reduced aggrecan mRNA/protein levels was observed in IACLR groups. As a result, the IACLR gross morphology score was dramatically increased than control. Moreover, IACLR significantly increased the levels of IL-1β, IL-4, IL-6 and TNF-α in the synovial fluid of the knee. Most importantly, a close relationship was found between IL-1β, IL-6 and TNF-α concentrations and morphological score of PTOA, respectively.

CONCLUSION
These results demonstrated that inflammatory factors are independently responsible for the onset of PTOA.

Han|Peng-Fei|PF| Wei|Lei|L| Duan|Zhi-Qing|ZQ| Zhang|Zhi-Liang|ZL| Chen|Tao-Yu|TY| Lu|Jian-Gong|JG| Zhao|Rui-Peng|RP| Cao|Xiao-Ming|XM| Li|Peng-Cui|PC| Lv|Zhi|Z| Wei|Xiao-Chun|XC|

D000070598:Anterior Cruciate Ligament Injuries

D059549:Anterior Cruciate Ligament Reconstruction

Anterior cruciate ligament reconstruction


The regulation of mitochondrial transcription factor A (Tfam) expression during skeletal muscle cell differentiation.

Abstract: The ATP demand required for muscle development is accommodated by elevations in mitochondrial biogenesis, through the co-ordinated activities of the nuclear and mitochondrial genomes. The most important transcriptional activator of the mitochondrial genome is mitochondrial transcription factor A (Tfam); however, the regulation of Tfam expression during muscle differentiation is not known. Thus, we measured Tfam mRNA levels, mRNA stability, protein expression and localization and Tfam transcription during the progression of muscle differentiation. Parallel 2-fold increases in Tfam protein and mRNA were observed, corresponding with 2-3-fold increases in mitochondrial content. Transcriptional activity of a 2051 bp promoter increased during this differentiation period and this was accompanied by a 3-fold greater Tfam mRNA stabilization. Interestingly, truncations of the promoter at 1706 bp, 978 bp and 393 bp promoter all exhibited 2-3-fold higher transcriptional activity than the 2051 bp construct, indicating the presence of negative regulatory elements within the distal 350 bp of the promoter. Activation of AMP kinase augmented Tfam transcription within the proximal promoter, suggesting the presence of binding sites for transcription factors that are responsive to cellular energy state. During differentiation, the accumulating Tfam protein was progressively distributed to the mitochondrial matrix where it augmented the expression of mtDNA and COX (cytochrome c oxidase) subunit I, an mtDNA gene product. Our data suggest that, during muscle differentiation, Tfam protein levels are regulated by the availability of Tfam mRNA, which is controlled by both transcription and mRNA stability. Changes in energy state and Tfam localization also affect Tfam expression and action in differentiating myotubes.

Collu-Marchese|Melania|M|
Shuen|Michael|M|
Pauly|Marion|M|
Saleem|Ayesha|A|
Hood|David A|DA|

D055372:AMP-Activated Protein Kinases
D000620:Aminoimidazole Carboxamide
D000818:Animals
D001665:Binding Sites
D002454:Cell Differentiation
D002460:Cell Line
D004268:DNA-Binding Proteins
D003576:Electron Transport Complex IV
D005786:Gene Expression Regulation
D006609:High Mobility Group Proteins
D051379:Mice
D008931:Mitochondria, Muscle
D018482:Muscle, Skeletal
D011401:Promoter Regions, Genetic
D020871:RNA Stability
D012265:Ribonucleotides

messenger ribonucleic acid (mRNA) stability


Irradiation-induced senescence of bone marrow mesenchymal stem cells aggravates osteogenic differentiation dysfunction via paracrine signaling.

Abstract: The role of cellular senescence induced by radiation in bone loss has attracted much attention. As one of the common complications of anticancer radiotherapy, irradiation-induced bone deterioration is common and clinically significant, but the pathological mechanism has not been elucidated. This study was performed to explore the cellular senescence and senescence-associated secretory phenotype (SASP) induction of bone marrow-derived mesenchymal stem cells (BMSCs) by irradiation and its role in osteogenic differentiation dysfunction. It was observed that irradiated BMSCs lost typical fibroblast-like morphology, exhibited suppressed viability and differentiation potential accompanied with senescence phenotypes, including an increase in senescence-associated β-galactosidase (SA-β-gal) staining-positive cells, and upregulated senescence-related genes p53/p21, whereas no changes happened to p16. Additionally, DNA damage γ-H2AX foci, G0/G1 phase of cell cycle arrest, and cellular and mitochondrial reactive oxygen species (ROS) increased in an irradiation dose-dependent manner. Meanwhile, the JAK1/STAT3 pathway was activated and accompanied by an increase in SASP secretion, such as IL-6, IL-8, and matrix metalloproteinase-9 (MMP9), whereas 0.8 μM JAK1 inhibitor (JAKi) treatment effectively inhibited the JAK pathway and SASP production. Furthermore, conditioned medium (CM) from irradiation-induced senescent (IRIS) BMSCs exhibited a markedly reduced ability in osteogenic differentiation and marker gene expression of osteoblasts, whereas CM with JAKi intervention may effectively improve these deterioration effects. In conclusion, irradiation could provoke BMSC senescence and SASP secretion and further aggravate osteogenic differentiation dysfunction via paracrine signaling, whereas SASP targeting may be a possible intervention strategy for alleviating irradiation-induced bone loss.

Bai|Jiangtao|J|0000-0002-5999-6282 Wang|Yuyang|Y| Wang|Jianping|J| Zhai|Jianglong|J| He|Feilong|F| Zhu|Guoying|G|

D018507:Gene Expression Regulation, Developmental

bone marrow mesenchymal stem cells
osteogenic differentiation
cellular senescence
SASP
irradiation


Increased glutamic acid decarboxylase expression in the hypothalamic suprachiasmatic nucleus in depression.

Abstract: In depression, disrupted circadian rhythms reflect abnormalities in the central circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN). Although many SCN neurons are said to be GABAergic, it was not yet known whether and how SCN GABA changes occur in the SCN in depression. We, therefore, studied GABA in the SCN in relation to the changes in arginine vasopressin (AVP), which is one of the major SCN output systems. Postmortem hypothalamus specimens of 13 subjects suffering from depression and of 13 well-matched controls were collected. Quantitative immunocytochemistry was used to analyze the protein levels of glutamic acid decarboxylase (GAD)65/67 and AVP, and quantitative in situ hybridization was used to measure transcript levels of GAD67 in the SCN. There were a significant 58% increase of SCN GAD65/67-ir and a significant 169% increase of SCN GAD67-mRNA in the depression group. In addition, there were a significant 253% increase of AVP-ir in female depression subjects but not in male depression patients. This sex difference was supported by a re-analysis of SCN AVP-ir data of a previous study of our group. Moreover, SCN-AVP-ir showed a significant negative correlation with age in the control group and in the male, but not in the female depression group. Given the crucial role of GABA in mediating SCN function, our finding of increased SCN GABA expression may significantly contribute to the disordered circadian rhythms in depression. The increased SCN AVP-ir in female-but not in male-depression patients-may reflect the higher vulnerability for depression in women.

Wu|Xueyan|X|
Balesar|Rawien|R|
Lu|Jing|J|
Farajnia|Sahar|S|
Zhu|Qiongbin|Q|
Huang|Manli|M|
Bao|Ai-Min|AM|
Swaab|Dick F|DF|

Suprachiasmatic nucleus
Depression
GABA
Arginine vasopressin
Sex difference


Effects of footshocks on anxiety-like behavior and mRNA levels of precursor peptides for corticotropin releasing factor and opioids in the forebrain of the rat.

Abstract: Corticotropin releasing factor (CRF) and dynorphin are neuropeptides that are associated with the negative emotional states. Experimental evidence indicates that dynorphin neurons located in the nucleus accumbens and CRF neurons in the bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (CeA) mediate anxiety-like behaviors immediately after the stressful experience (24-48h). The present study was done to evaluate if changes in the levels of the mRNA for these peptides in the striatum, BST, and CeA were associated with the long-lasting avoidance of novelty, a measure of an anxiety-like state, in a subset of rats exposed to unpredictable and moderately intense footshocks (5×2s of 1.5mA). Shocked rats with enhanced fear to a novel tone 24h after the footshocks (high responders; HR) displayed long-lasting avoidance in the elevated T-maze whereas shocked rats with low levels of acute fear (low responders; LR) had low levels of avoidance similar to nonshocked rats. An increase in the level of proCRF mRNA was detected in the CeA of the HR compared to LR and nonshocked rats but not in other areas of the brain sampled. In contrast, prodynorphin and proenkephalin mRNA levels in the striatum, BST and CeA were not different between HR, LR and nonshocked rats. This study provides evidence that CRF neurons in the CeA may play a role in the anxiety-like state produced in a subset of rats exposed to footshocks.

Wang|Huiying|H|
Li|Sa|S|
Kirouac|Gilbert J|GJ|

Corticotropin releasing factor
Dynorphin
Bed nucleus of the stria terminalis
Amygdala
Striatum
Anxiety
Enkephalin


Calreticulin is highly expressed in pancreatic cancer stem-like cells.

Abstract: Cancer stem-like cells (CSLCs) in solid tumors are thought to be resistant to conventional chemotherapy or molecular targeting therapy and to contribute to cancer recurrence and metastasis. In this study, we aimed to identify a biomarker of pancreatic CSLCs (P-CSLCs). A P-CSLC-enriched population was generated from pancreatic cancer cell lines using our previously reported method and its protein expression profile was compared with that of parental cells by 2-D electrophoresis and tandem mass spectrometry. The results indicated that a chaperone protein calreticulin (CRT) was significantly upregulated in P-CSLCs compared to parental cells. Flow cytometry analysis indicated that CRT was mostly localized to the surface of P-CSLCs and did not correlate with the levels of CD44v9, another P-CSLC biomarker. Furthermore, the side population in the CRThigh /CD44v9low population was much higher than that in the CRTlow /CD44v9high population. Calreticulin expression was also assessed by immunohistochemistry in pancreatic cancer tissues (n = 80) obtained after radical resection and was found to be associated with patients' clinicopathological features and disease outcomes in the Cox proportional hazard regression model. Multivariate analysis identified CRT as an independent prognostic factor for pancreatic cancer patients, along with age and postoperative therapy. Our results suggest that CRT can serve as a biomarker of P-CSLCs and a prognostic factor associated with poorer survival of pancreatic cancer patients. This novel biomarker can be considered as a therapeutic target for cancer immunotherapy.

Matsukuma|Satoshi|S| Yoshimura|Kiyoshi|K| Ueno|Tomio|T| Oga|Atsunori|A| Inoue|Moeko|M| Watanabe|Yusaku|Y| Kuramasu|Atsuo|A| Fuse|Masanori|M| Tsunedomi|Ryouichi|R| Nagaoka|Satoshi|S| Eguchi|Hidetoshi|H| Matsui|Hiroto|H| Shindo|Yoshitaro|Y| Maeda|Noriko|N| Tokuhisa|Yoshihiro|Y| Kawano|Reo|R| Furuya-Kondo|Tomoko|T| Itoh|Hiroshi|H| Yoshino|Shigefumi|S| Hazama|Shoichi|S| Oka|Masaaki|M| Nagano|Hiroaki|H|

calreticulin
pancreatic cancer
Biomarkers
cancer stem cells
proteomics


Risk factors for early postoperative complications in patients with Crohn's disease after colorectal surgery other than ileocecal resection or right hemicolectomy.

Abstract:
PURPOSE
To evaluate risk factors for early postoperative complications in patients with Crohn's disease (CD) after extensive colorectal resection excluding mere ileocecal resection or right hemicolectomy at a university center.

METHODS
A retrospective analysis of the prospectively maintained database for surgical patients with CD at our institution was performed. All consecutive patients operated between December 2009 and December 2017 were included.

RESULTS
In total, 126 patients were eligible for this study. Most common types of operations performed were subtotal colectomy or proctocolectomy (37.3%) and resections of the rectum (34.1%) or the sigmoid colon (14.3%). Major postoperative complications occurred in 29 patients (23.0%). The rate of local septic complications (anastomotic leak, postoperative abscess) was 11.1%. In univariate analysis, low preoperative albumin, elevated preoperative C-reactive protein (CRP), and emergency surgery were factors associated with major postoperative complications. When multivariable analysis was performed, low preoperative albumin was the only independent risk factor for the occurrence of major postoperative complications (p = 0.0033; OR 0.899). The cut-off value for albumin was 32.6 g/L.

CONCLUSIONS
In this large cohort of consecutive patients undergoing surgery of the colorectum in CD, the rate of major postoperative complications was considerably higher compared to our recently published data from patients with ileocecal resection or right hemicolectomy. Preoperative albumin is the only independent risk factor for the occurrence of major postoperative complications. Preoperative albumin levels > 32.6 g/L significantly reduce the risk for postoperative complications.

Galata|Christian|C| Kienle|Peter|P| Weiss|Christel|C| Seyfried|Steffen|S| Reißfelder|Christoph|C| Hardt|Julia|J|

Postoperative complications
Colectomy
Anastomotic leak
Crohn’s disease
Left hemicolectomy
Rectal surgery


Perceptions of couplehood among community-dwelling spousal caregivers.

Abstract: Objective: Spousal caregiving is increasingly common, and it is a role that can alter the nature of marriage in later life. Some may find spousal caregiving to be distressing, while others may have more positive experiences. Spousal caregiving, in particular, may be difficult due to caregiver burden as well as a loss of couplehood within the relationship. The current study used grounded theory methods to better understand the experience of and changes in couplehood among spousal caregivers.Method: Thirteen spousal caregivers completed semi-structured interviews. Spousal caregivers ranged in age from 53 to 85 (mean age = 66.00, SD = 9.04).Results: Qualitative analysis revealed four major themes upon evaluation of the interviews (couplehood, positive mindset, later life roles and transitions, and looking towards the future).Conclusion: These themes exemplified the complex interplay of couplehood and caregiving as well as the range of perceptions of couplehood. Results showed that while some caregivers struggle to find meaning and happiness within their caregiver role, and others said the illness/impairment bonded them together. Caregivers who reported a low sense couplehood discussed feeling trapped in their relationship, sad, and isolated. For some caregivers, a strong sense of couplehood may have helped them reframe the experience as an opportunity to be a role model for others and a reminder that their situation could be worse. Future research should focus on pre-illness couplehood and whether the nature of the impairment (e.g., cognitive, physical) is related to caregiver's couplehood.

Couplehood
spousal caregiver
caregiving
qualitative
community dwelling
older adult


Review of patient decision-making factors and attitudes regarding preimplantation genetic diagnosis.

Abstract: The increasing technical complexity and evolving options for repro-genetic testing have direct implications for information processing and decision making, yet the research among patients considering preimplantation genetic diagnosis (PGD) is narrowly focused. This review synthesizes the literature regarding patient PGD decision-making factors, and illuminates gaps for future research and clinical translation. Twenty-five articles met the inclusion criteria for evaluating experiences and attitudes of patients directly involved in PGD as an intervention or considering using PGD. Thirteen reports were focused exclusively on a specific disease or condition. Five themes emerged: (1) patients motivated by prospects of a healthy, genetic-variant-free child, (2) PGD requires a commitment of time, money, energy and emotions, (3) patients concerned about logistics and ethics of discarding embryos, (4) some patients feel sense of responsibility to use available technologies, and (5) PGD decisions are complex for individuals and couples. Patient research on PGD decision-making processes has very infrequently used validated instruments, and the data collected through both quantitative and qualitative designs have been inconsistent. Future research for improving clinical counseling is needed to fill many gaps remaining in the literature regarding this decision-making process, and suggestions are offered.

Genoff Garzon|M C|MC|
Rubin|L R|LR|
Lobel|M|M|
Stelling|J|J|
Pastore|L M|LM|

reproductive endocrinology and infertility


Modeling of gonioscopic anterior chamber angle grades based on anterior segment optical coherence tomography.

Abstract:
Background
To quantitatively assess anterior chamber angle (ACA) structure by anterior segment optical coherence tomography (AS-OCT) and develop a model to evaluate angle width as defined by gonioscopy.

Methods
The ACAs of each quadrant were evaluated by gonioscopy, classified by the Scheie grading system, and assigned into one of the three grades: small angle (SA), moderate angle (MA), and large angle (LA). The eyes were imaged by AS-OCT, and ACA structural parameters including angle opening distance at the scleral spur (AODSS) and at 750 μm anterior to the scleral spur (AOD750), trabecular-iris space area at 750 μm anterior to the scleral spur (TISA750), and a newly defined parameter "light intersection distance" (LID), were measured. The ACA structural data were used to construct an ordered logistic regression model for assignment of ACAs to one of the three angle grades. The validity of the model was then tested.

Results
A total of 169 quadrants from 53 subjects were included in the analysis, of which 111 quadrants were included in the modeling data and 58 in the testing data. In pairwise comparisons of SA, MA, and LA by ANOVA, the measured parameters were as follows: AOD750 (0.174 ± 0.060 vs. 0.249 ± 0.068 vs. 0.376 ± 0.114 mm; P < 0.001), TISA750 (0.075 ± 0.035 vs. 0.117 ± 0.036 vs. 0.181 ± 0.062 mm2; P < 0.001), and LID (- 0.300 ± 0.187 vs. -0.085 ± 0.170 vs. 0.122 ± 0.156 mm; P < 0.001). The ACA grading model based on LID showed a relatively high correction rate of 72.4%, and the model efficiency, calculated using the receiver operating characteristic, showed an area under the curve of 0.740. Weighted kappa statistics showed a good agreement for multiple ACA grades (0.772).

Conclusions
The AS-OCT-based multiple ACA grades model was demonstrated as a non-contact approach for ACA assessment with high speed and high spatial resolution, providing guidance for diagnosis of angle closure.

Dai|Yingying|Y| Zhang|Shaodan|S| Shen|Meixiao|M| Zhou|Yuheng|Y| Wang|Mengyi|M| Ye|Jie|J| Zhu|Dexi|D|0000-0001-5553-2088


Integration of read-across and artificial neural network-based QSAR models for predicting systemic toxicity: A case study for valproic acid.

Abstract: We present a systematic, comprehensive and reproducible weight-of-evidence approach for predicting the no-observed-adverse-effect level (NOAEL) for systemic toxicity by using read-across and quantitative structure-activity relationship (QSAR) models to fill gaps in rat repeated-dose and developmental toxicity data. As a case study, we chose valproic acid, a developmental toxicant in humans and animals. High-quality in vivo oral rat repeated-dose and developmental toxicity data were available for five and nine analogues, respectively, and showed qualitative consistency, especially for developmental toxicity. Similarity between the target and analogues is readily defined computationally, and data uncertainties associated with the similarities in structural, physico-chemical and toxicological properties, including toxicophores, were low. Uncertainty associated with metabolic similarity is low-to-moderate, largely because the approach was limited to in silico prediction to enable systematic and objective data collection. Uncertainty associated with completeness of read-across was reduced by including in vitro and in silico metabolic data and expanding the experimental animal database. Taking the "worst-case" approach, the smallest NOAEL values among the analogs (i.e., 200 and 100 mg/kg/day for repeated-dose and developmental toxicity, respectively) were read-across to valproic acid. Our previous QSAR models predict repeated-dose NOAEL of 148 (males) and 228 (females) mg/kg/day, and developmental toxicity NOAEL of 390 mg/kg/day for valproic acid. Based on read-across and QSAR, the conservatively predicted NOAEL is 148 mg/kg/day for repeated-dose toxicity, and 100 mg/kg/day for developmental toxicity. Experimental values are 341 mg/kg/day and 100 mg/kg/day, respectively. The present approach appears promising for quantitative and qualitative in silico systemic toxicity prediction of untested chemicals.

Hisaki|Tomoka|T|
Kaneko|Maki Aiba Née|MAN|
Hirota|Morihiko|M|
Matsuoka|Masato|M|
Kouzuki|Hirokazu|H|

No Observed Adverse Effect Level (NOAEL)


Hypertension and diabetes mellitus as risk factors for asthma in Korean adults: the Sixth Korea National Health and Nutrition Examination Survey.

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

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

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

CONCLUSIONS
Age, sex, hypertension, SBP, DM, HbA1c and insulin levels are all factors that may influence the occurrence of asthma in Korean adults. In particular, hypertension and diabetes emerge from the present study as potential associated factors for the development of asthma.

hypertension
diabetes mellitus
asthma
blood pressure
haemoglobin A1c
insulin


Prospects for using a hemoconcentrator as an alternative hemodialysis method in cardiopulmonary bypass surgeries.

Abstract:
OBJECTIVE
Cardioplegic solutions often cause high blood concentrations of potassium. The conventional hemoconcentration circuit was improved to correct electrolyte imbalances through a method involving dilutional ultrafiltration (DUF) and an alternative hemodialysis (ALTHD) method. This study aimed to determine the effectiveness of this ALTHD method.

METHODS
Bovine blood was used, in conjunction with a hemoconcentrator, in an experimental hemodialysis (HD) circuit to evaluate an ALTHD method. The effectiveness of the method was determined by electrolyte and hematocrit measurements following the procedure.

RESULTS
The ALTHD method corrected electrolyte levels as effectively as DUF and was less affected by dilution than DUF.

CONCLUSION
The ALTHD method may provide faster electrolyte adjustments than DUF because its efficiency depends on both the blood and dialysate flow rates. In addition, the ALTHD method is expected to provide increased efficiency. Thus, our DUF/ALTHD circuit-switching method may be clinically useful when rapid electrolyte correction is required.

Tagaya|M|M| Matsuda|M|M| Yakehiro|M|M| Izutani|H|H|

hemoconcentrator
hemodialysis
cardiopulmonary bypass
dilutional ultrafiltration
hyperkalemia


Mastering analytical challenges for the characterization of pentacyclic triterpene mono- and diesters of Calendula officinalis flowers by non-aqueous C30 HPLC and hyphenation with APCI-QTOF-MS.

Abstract: Pentacyclic triterpene mono- and diesters have been isolated from Calendula officinalis flowers. GC-MS, APCI-Exactive Orbitrap HR-MS and NMR allowed to identify the triterpene skeleton in various samples (different triterpene mixtures from Calendula n-hexane extract). NMR provided evidence that triterpene diesters are present in the samples as well. However, the corresponding quasi-molecular ions could not be detected by APCI-Exactive Orbitrap HR-MS. Instability of triterpene diesters and loss of a fatty acid residue, respectively, in the ion-source made their MS detection challenging. Thus, a set of new APCI-QTOF-MS methods (using the TripleTOF 5600+ mass spectrometer) were developed which made it eventually possible to solve this problem and confirm the diester structures by MS via quasi-molecular ion [M+H](+) detection. Direct infusion APCI-QTOF MS experiments in MS/MS high sensitivity scan mode with low collision energy and multi-channel averaging acquisition (MCA) allowed the detection of quasi-molecular ions of triterpene diesters for the first time and unequivocally confirmed the presence of faradiol 3,16-dimyristate and -dipalmitate, as well as the corresponding mixed diesters faradiol 3-myristate,16-palmitate and faradiol 3-palmitate,16-myristate. Preferential loss of the fatty acid in 16-position made it possible to distinguish the mixed diesters by MS/MS spectra. Their chromatographic separations turned out to be challenging due to their bulkiness and extended molecular dimensions. However, separation could be achieved by an uncommon non-aqueous RPLC mode with an in-house synthesized C30 phase. Finally, two (U)HPLC-APCI-QTOF-MS methods with C18- and C30-based non-aqueous RPLC provided suitable, sensitive assays to monitor the presence of monoesters and diesters of various triterpenes (faradiol, maniladiol, arnidiol, arnitriol A and lupane-3β,16β,20-triol esters) in the n-hexane extract of C. officinalis with high mass resolution and good mass accuracy.

Nicolaus|Christoph|C| Sievers-Engler|Adrian|A| Murillo|Renato|R| D'Ambrosio|Michele|M| Lämmerhofer|Michael|M| Merfort|Irmgard|I|

D002851:Chromatography, High Pressure Liquid

Calendula officinalis
non-aqueous RPLC
(U)HPLC-APCI-QTOF-MS
C30 stationary phase
Triterpene mono- and novel diesters


Identification and characterization of in vitro and in vivo generated metabolites of the adiponectin receptor agonists AdipoRon and 112254.

Abstract: Peroxisome proliferator-activated receptors (PPARs), peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), sirtuin 1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK) are regulators of transcriptional processes and effects of exercise and pseudo-exercise situations. Compounds occasionally referred to as endurance exercise mimetics such as AdipoRon and 112254, both adiponectin receptor agonists, can be used to simulate the physiology of endurance exercise via pathways including these transcriptional regulators. Adiponectin supports fatty acid utilization and triglyceride-content reduction in cells and increases both the mitochondrial biogenesis and the oxidative metabolism in muscle cells. In routine doping control analysis, knowledge about phase-I and -II metabolic products of target analytes is essential. Hence, in vitro- and in vivo-metabolism experiments are frequently employed tools in preventive doping research to determine potential urinary metabolites for sports drug testing purposes, especially concerning new, (yet) unapproved compounds. In the present study, in vitro assays were conducted using human liver microsomal and S9 fractions, and rat in vivo experiments were performed using both AdipoRon and 112254. For AdipoRon, obtained samples were analyzed using liquid chromatography-high resolution/high accuracy (tandem) mass spectrometry with both electrospray ionization or atmospheric-pressure chemical ionization techniques. Overall, more than five phase I-metabolites were found in vitro and in vivo, including particularly monohydroxylated and hydrogenated species. No phase II-metabolites were found in vitro; conversely, signals suggesting the presence of glucuronic acid or other conjugates in samples collected from in vivo experiment were observed, the structures of which were however not conclusively identified. Also for 112254, several phase-I metabolites were found in vitro, e.g. monohydroxylated and demethylated species. Here, no phase II-metabolites were observed neither using in vitro nor in vivo samples. Based on the generated data, the implementation of metabolites and unmodified drug candidates into routine doping control protocols is deemed warranted for comprehensive sports drug testing programs until human elimination study data are available.

Dib|Josef|J| Thomas|Andreas|A| Delahaut|Philippe|P| Fichant|Eric|E| Schänzer|Wilhelm|W| Thevis|Mario|M|

Exercise mimetic
Metabolism
Doping
Sport
Mass spectrometry


Statin use and its potential therapeutic role in esophageal cancer: a systematic review and meta-analysis.

Abstract: Purpose: Statins, known as inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductases, are designed to treat lipid disorders, especially hypercholesterolemia. Apart from their role in preventing heart diseases in patients with high cholesterol, recent evidence suggests that statins have anti-tumor properties. However, studies assessing the association between statin use and esophageal cancer survival outcomes have provided controversial results. Methods: We conducted a systematic review and meta-analysis focusing on studies evaluating associations between statin use and survival outcomes for esophageal cancer patients. Results: A total of five cohort studies comprising 24,576 patients were included. Statin use associated with improved overall survival (OS: HR 0.84, 95% CI, 0.75-0.94) and disease-free survival (DFS: HR 0.84, 95% CI, 0.75-0.96) of esophageal cancer patients. The improved survival outcomes were consistent in the esophageal adenocarcinoma subgroup and the esophageal squamous cell cancer subgroup. Conclusion: A potential therapeutic role of statins in esophageal cancer has been demonstrated in our study, however, the results should be interpreted cautiously and need further confirmation by future studies.

Zhou|Cen|C| Zhong|Xi|X| Gao|Peng|P| Wu|Zhonghua|Z| Shi|Jinxin|J| Guo|Zhexu|Z| Wang|Zhenning|Z| Song|Yongxi|Y|

statins
esophageal cancer
survival outcome
drug repositioning