bluuebunny/crossref_metadata_2025 huggingface dataset:
Education versus screening: the use of capacity to consent tools in psychiatric genomics
Authors: Kong Camillia , Efrem Mehret , Campbell Megan
Published: September 2019

Informed consent procedures for participation in psychiatric genomics research among individuals with mental disorder and intellectual disability can often be unclear, particularly because the underlying ethos guiding consent tools reflects a core ethical tension between safeguarding and inclusion. This tension reflects important debates around the function of consent tools, as well as the contested legitimacy of decision-making capacity thresholds to screen potentially vulnerable participants. Drawing on human rights, person-centred psychiatry and supported decision-making, this paper problematises the use of consent procedures as screening tools in psychiatric genomics studies, particularly as increasing normative emphasis has shifted towards the empowerment and participation of those with mental disorder and intellectual disabilities. We expound on core aspects of supported decision-making, such as relational autonomy and hermeneutic competence, to orient consent procedures towards a more educative, participatory framework that is better aligned with developments in disability studies. The paper concludes with an acknowledgement of the pragmatic and substantive challenges in adopting this framework in psychiatric genomics studies if this participatory ethos towards persons with mental disorder and intellectual disability is to be fully realised.
The ethics of testing and research of manufactured organs on brain-dead/recently deceased subjects
Authors: Parent Brendan , Gelb Bruce , Latham Stephen , Lewis Ariane , Kimberly Laura L , Caplan Arthur L
Published: September 2019

Over 115 000 people are waiting for life-saving organ transplants, of whom a small fraction will receive transplants and many others will die while waiting. Existing efforts to expand the number of available organs, including increasing the number of registered donors and procuring organs in uncontrolled environments, are crucial but unlikely to address the shortage in the near future and will not improve donor/recipient compatibility or organ quality. If successful, organ bioengineering can solve the shortage and improve functional outcomes. Studying manufactured organs in animal models has produced valuable data, but is not sufficient to understand viability in humans. Before risking manufactured organ experimentation in living humans, study of bioengineered organs in recently deceased humans would facilitate evaluation of the function of engineered tissues and the complex interactions between the host and the transplanted tissue. Although such studies do not pose risk to human subjects, they pose unique ethical challenges concerning the previous wishes of the deceased, rights of surviving family members, effective operation and fair distribution of medical services, and public transparency. This article investigates the ethical, legal and social considerations in performing engineered organ research on the recently deceased.
Effects of first pass recanalization on outcomes of contact aspiration thrombectomy
Authors: Kang Dong-Hun , Kim Byung Moon , Heo Ji Hoe , Nam Hyo Suk , Kim Young Dae , Hwang Yang Ha , Kim Yong-Won , Kim Dong Joon , Kim Joon Whi , Baek Jang-Hyun , Kim Yong-Sun
Published: September 2019

Background

First pass recanalization (FPR, defined as achieving a modified Thrombolysis in Cerebral Ischemia (mTICI) grade 2c/3 with a single pass of a thrombectomy device) effect has not yet been evaluated in contact aspiration thrombectomy (CAT). We evaluated FPR effect on clinical outcomes and FPR predictors in CAT.

Methods

All consecutive patients who underwent frontline CAT for anterior circulation large vessel occlusion with recanalization (mTICI 2b–3) were identified from registries at six stroke centers. The patients were dichotomized into FPR and non-FPR groups. Clinical features and outcomes were compared between the groups. Multivariate analyses were performed to determine whether FPR was independently associated with clinical outcomes and to identify predictors of FPR.

Results

Of the 429 patients who underwent frontline CAT, recanalization was successful in 344 patients (80.2%; mean age 68.7±11.0 years; M:F ratio 179:165). The FPR group had a higher rate of good outcome (modified Rankin Scale score 0–2) than the non-FPR group. Furthermore, the good outcome rate was higher in the FPR group than in patients who achieved mTICI 2c/3 with multiple passes or rescue treatment. FPR (OR 2.587; 95% CI 1.237 to 5.413) remained independently associated with good outcomes, in addition to age, baseline National Institute Health Stroke Scale, and coronary artery disease. The use of a balloon guide catheter (OR 3.071; 95% CI 1.699 to 5.550) was the only predictor of FPR.

Conclusions

Patients in the FPR group had better clinical outcomes than the non-FPR group in CAT. FPR was independently associated with a good outcome. The use of a balloon guide catheter was the only predictor of FPR.
Microcatheter shaping using three-dimensional printed models for intracranial aneurysm coiling
Authors: Xu Y , Tian W , Wei Z , Li Y , Gao X , Li W , Dong B
Published: September 2019

Background and purpose

Microcatheterization is an important, but also difficult, technique used for the embolization of intracranial aneurysms. The purpose of this study was to investigate the application of three-dimensional (3D) printing technology in microcatheter shaping.

Methods

Nine cases of internal carotid artery posterior communicating artery aneurysm diagnosed by CT angiography were selected, and 3D printing technology was used to build a 3D model including the aneurysm and the parent artery. The hollow and translucent model had certain flexibility; it was immersed in water and the microcatheter was introduced into the water to the target position in the aneurysm, followed by heating the water temperature to 50°C. After soaking for 5 min, the microcatheter was taken out and the shaping was completed. After sterilization, the shaped microcatheter was used for arterial aneurysm embolization and evaluation was conducted.

Results

Nine cases of microcatheter shaping were satisfactory and shaping the needle was not necessary; no rebound was observed. The microcatheter was placed in an ideal position, and the stent-assisted method was used in three cases of wide-neck aneurysm. There were no complications related to surgery.

Conclusion

A new microcatheter shaping method using 3D printing technology makes intracranial artery aneurysm embolization more stable and efficient.
Environmental exposures in young adults with declining kidney function in a population at risk of Mesoamerican nephropathy
Authors: Smpokou Evangelia-Theano , González-Quiroz Marvin , Martins Carla , Alvito Paula , Le Blond Jennifer , Glaser Jason , Aragón Aurora , Wesseling Catharina , Nitsch Dorothea , Pearce Neil , Norman Jill , Lindh Christian H , Morton Jackie , Caplin Ben
Published: September 2019

Objectives

There is an epidemic of Mesoamerican nephropathy (MeN) in Central America, where sugarcane production is prominent. Numerous causes are proposed, but to date limited evidence supports any one hypothesis. A nested case–control study using biosamples from a rural, community-based follow-up study of 350 young adults from Northwest Nicaragua at risk of MeN was conducted with the aim of characterising the associations between urinary concentrations of metals, pesticides and mycotoxins from samples collected in the first 6 months and decline in kidney function over 2 years.

Methods

Urine samples collected at baseline (pre-sugarcane harvest) and the first 6 month follow-up (post-sugarcane harvest) visit were tested. Twelve metals and metalloids (aluminium, total arsenic, cadmium, chromium, cobalt, copper, lead, manganese, mercury, selenium, silicon and strontium) were analysed by inductively coupled plasma-mass spectrometry. Twelve pesticides or their metabolites (2,4-dichlorophenoxyacetic acid, 3-phenoxybenzoic acid, 4-fluoro-3-phenoxybenzoic acid, chloro-3,3,3-trifluoro-1-propen-1-yl-2,2-dimethylcyclopropanecarboxylic acid, cis/trans 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid, ethylenethiourea, glyphosate, 4-chloro-2-methylphenoxy acetic acid, 3-hydroxy-pyrimetanil, 5-hydroxytiabendazole, hydroxy-tebuconazole and 3,5,6-trichloro-2-pyridinol) and two mycotoxins (ochratoxin A (OTA) and citrinin (CIT)) were analysed by liquid chromatography coupled-mass spectrometry. Differences in the creatinine-corrected urinary concentrations of the measured exposures between outcome groups (participants with stable vs declining kidney function) were examined.

Results

Elevated levels of aluminium and total arsenic as well as metabolites of several pesticides were detected across the population. No differences were identified between the declining and stable groups in the levels of metals or pesticides tested. OTA and CIT were below the limit of detection.

Conclusions

The tested metals, metalloids, pesticides and mycotoxins were not associated with loss of kidney function in participants at-risk of MeN.
Association of adiponectin and adiponectin receptor gene polymorphisms with rheumatoid arthritis in a Chinese population
Authors: Zhao Yu-Lan , Zhang Tian-Ping , Wu Jun , Li Bao-Zhu , Li Xiao-Mei , Pan Hai-Feng , Ye Dong-Qing
Published: September 2019

Purpose

To explore the association of adiponectin (AD) and adiponectin receptor (ADR) gene single-nucleotide polymorphisms (SNPs) with genetic susceptibility to rheumatoid arthritis (RA) in a Chinese population.

Study design

Five AD SNPs (rs266729, rs2241766, rs1063537, rs2082940 and rs1063539) and two ADR SNPs (rs7539542 and rs12342) were genotyped in a cohort of 617 patients with RA and 639 healthy controls. Seven SNPs were genotyped using TaqMan genotyping assays on the Fluidigm 192.24 system. The concentration of AD in plasma was examined by ELISA.

Results

Patients with RA showed a considerably lower plasma level of AD than healthy controls (p=0.002). No significant differences were observed for the distribution of allele and genotype frequencies of rs266729, rs2241766, rs2082940, rs1063539, rs7539542 and rs12342 SNPs between patients with RA and controls. The genotype effects of recessive and dominant models were also analysed, but no marked evidence for association was found. However, further analysis in female patients with RA showed that the frequency of the AD gene rs1063539 GG genotype was nominally significantly higher in patients who were anti-cyclic citrullinated peptide (anti-CCP) antibody-positive (p=0.040). No significant differences in serum AD level were observed in patients with RA with different genotypes.

Conclusions

rs266729, rs2241766, rs2082940 and rs1063539 in the AD gene and rs7539542 and rs12342 in the ADR gene are possibly not associated with genetic susceptibility to RA, but the AD gene rs1063539 locus was possibly associated with anti-CCP in RA female patients.
Factors influencing pharmacists’ over-the-counter drug recommendations
Authors: Grebenar Darija , Nham Eric , Likic Robert
Published: September 2019

Background

Self-care is a growing trend all over the world, and pharmacists have a major role in it since they are the most easily accessible medical experts.

Objectives

Our aim was to investigate factors influencing pharmacists’ over-the-counter (OTC) drugs recommendations in Croatia.

Setting

A random sample of 565 (50%) of all pharmacies in Croatia.

Methods

A cross-sectional study with a five-point Likert scale online questionnaire covering medical and non-medical factors influencing OTC drug recommendation was distributed in October 2017 to a random sample of pharmacies.

Results

206/565 (response rate 36.5%) responses were collected. The most important factors influencing pharmacists’ recommendation were: composition of the OTC product and its active component (4.76±0.47), scientific evidence of effectiveness (4.54±0.60), feedback from the patients (4.32±0.61) and information from professional journals (4.22±0.67). On average, medical factors had greater importance (4.5±0.58) for pharmacists’ OTC recommendation than marketing (3.18±0.84) and social factors (3.15±0.79). Female pharmacists appeared less inclined to recommend an OTC product based on advice of other pharmacists (OR=0.61, CI=0.43 to 0.86, p=0.005) and pharmacists working directly in a pharmacy attached more importance to active components of OTC products during their OTC product counselling (OR=2.28, CI=0.92 to 5.65, p=0.03).

Conclusion

It is vital to know that pharmacists’ OTC recommendations are mainly influenced by medical factors and to a lesser degree by marketing and social factors.
Prospective cohort study examining the use of regional anesthesia for early pain management after combat-related extremity injury
Authors: Gallagher Rollin M , Polomano Rosemary C , Giordano Nicholas A , Farrar John T , Guo Wensheng , Taylor Lynn , Oslin David , Goff Brandon J , Buckenmaier Chester C
Published: September 2019

Background

No studies have examined the long-term benefits of regional anesthesia (RA) for pain management after combat-related injury. The objective of this prospective cohort study was to examine the relationship between RA administration and patient-reported pain-related outcomes among Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) service members sustaining a combat-related extremity injury.

Methods

Between 2007 and 2013, n=358 American military personnel injured in OEF/OIF were enrolled at two military treatment facilities. Individuals were followed for up to 2 years after injury. Cohorts were defined based on whether participants were administered RA within 7 days after sustaining a combat-related injury, or not. Linear mixed effects models examined the association between RA and average pain intensity. Secondary outcomes included pain relief, pain interference, neuropathic pain symptoms, treatment outcomes related to pain management, and mental health symptoms.

Results

Receiving early RA was associated with improved average pain over the first 6 months after injury (β=−0.57; p=0.012) adjusting for injury severity and length of stay at the primary treatment facility. This difference was observed up to 24 months after injury (β=−0.36; p=0.046). Individuals receiving early RA reported greater pain relief, improved neuropathic pain intensity, and higher satisfaction with pain outcomes; however, by 24 months, mean scores did not significantly differ between cohorts.

Conclusion

Findings indicate that when administered soon after traumatic injury, RA is a valuable pain management intervention. Future longitudinal studies investigating the timely delivery of RA for optimal pain management in civilian trauma settings are needed.

Trial registration number

NCT00431847
Bolus epidural infusion improves spread compared with continuous infusion in a cadaveric porcine spine model
Authors: Cole Jacob , Hughey Scott
Published: September 2019

Background

The administration of epidural anesthesia during labor is a common technique used to reduce the pain of childbirth. We sought to compare standard infusion strategies of continuous epidural infusions (CEI) with programmed intermittent epidural bolus (PIEB) to assess the length of spread in terms of vertebral body length. Based on previous clinical data in humans, the PIEB was associated with improved pain control and decreased total dose of local anesthetic. We hypothesized that the PIEB was associated with increased spread when compared with CEI.

Methods

Thirty female Yorkshire-cross swine cadavers were used to compare three infusion strategies, continuous infusion (CEI) 10 mL/hour programmed continuously, multiple bolus (MB) 2 mL given every 12 min for 10 mL total and 10 mL delivered in a single bolus (SB). Radiographs were used to identify the spread of the radiopaque contrast dye, and a number of vertebral bodies covered were measured to assess spread.

Results

Overall, the CEI had an average spread of 5.6 levels, MB 7.9 and SB 10.4. The differences between SB and MB (p=0.011), SB and CEI (p<0.001) and MB and CEI (p=0.028) were all found to be significant.

Conclusions

We demonstrated increased spread of epidural contrast with programmed intermittent bolus strategies. This supports previous evidence of improved patient outcomes with PIEB strategy compared with CEI, and encourages the use of PIEB in the appropriate patient population.
Salmonella contamination in a network of 10 pig farms interconnected within the same cooperative
Authors: Henry Alexandra , Letellier Ann , Côté Jean‐Charles , Desmarais Gabriel , Lachapelle Virginie , Bergeron Nadia , Lewandowsky Sylvette , Fravalo Philippe
Published: September 2019

Objective

To evaluate whether pig farms interconnected within the same cooperative share similar Salmonella contamination patterns.

Setting

Ten finishing pig farms within a 100 km radius of a common slaughterhouse were selected. Their inclusion was based on their association to the same cooperative and the sharing of common resources: piglets, feed, swine transporters, slaughterhouse, technicians and veterinarians.

Procedure

Each farm was visited three times over a 10‐month period. Pig faeces, the barn front door handle, the feed pipeline, mobile objects (shovel, balance and pig board), the landing stage, the concrete slab of the feed bins, the tire tracks left on the pathways by the animal feed truck, the pig delivery truck and the carcase knacker truck and the mudguards and cabin carpets of the veterinarian and technician vehicles on their arrival at the farm were all analysed for the presence of Salmonella.

Results

All farms were not equally contaminated with Salmonella. Whereas some farms yielded up to 12 Salmonella isolates, other farms were Salmonella free. Some locations, most notably the landing stage, were more contaminated than others. Salmonella contamination was dynamic in time. Some contaminations seen on farms, on specific locations on the first visit, had disappeared on the second and third visits, but new contaminations were detected on different locations.

Conclusions

Contamination with Salmonella was not disseminated through the network of the 10 pig farms interconnected within the same cooperative but was rather most often restricted in time to specific locations on specific farms.
West Nile fever in Europe in 2018: an emerging problem or just an anomaly?
Authors: Browne Christopher , Medlock Jolyon M.
Published: September 2019

Last summer saw an unusually high number of cases of West Nile fever in horses and people in south and south‐east Europe, but it is too early to tell if this was a one‐off increase or a sign of things to come. Here, Christopher Browne, Eleanor Glendenning, Jolyon Medlock and Helen Roberts discuss the various West Nile fever surveillance and control mechanisms in place in the UK.
Development of retrotransposons insertion polymorphic markers and application in the genetic variation evaluation of Chinese Bama miniature pigs
Authors: Zhang Li , wang xiaoyan , Chen Cai , Wang Wei , Yang Kunlun , Shen Dan , Wang Saisai , gao bo , Guo Yafen , Mao Jiude , song Chengyi
Published: September 2019

Retrotransposons are genetic elements that can amplify themselves in a genome and are abundant in many eukaryotic organisms. In this study, we established some new short interspersed nuclear elements (SINE) and endogenous retroviruses (ERV) retrotransposons insertion polymorphism (RTIP) markers based on BLAT alignment tool strategy, and followed by PCR evaluation. We investigated the genetic variations among four subpopulations of Chinese Bama miniature pigs (BM), including BM in national conservation farm (BM-cov), BM inbreeding population (BM-inb) and BM closed Herd (BM-clo) in Guangxi University, and BM in the Experimental pig farm of Yangzhou University (BM-yzu). Genetic distance, polymorphism information content (PIC) and heterozygosity (He) of these markers in four of BM subpopulations were measured. Twelve SINE and twenty-eight ERV polymorphic molecular markers were identified in the four subpopulations. The BM-cov pigs represented the highest He and PIC, which indicated that BM-cov pigs maintain relatively highly genetic diversity. BM-inb pigs represented the lowest He and PIC indicating less variation and a high degree of inbreeding. Microsatellites polymorphism in four BM populations also well supported the results of these RTIP markers. In summary, retrotransposons insertion polymorphic markers could be a useful tool for population genetic variation analysis. Current SINE and ERV variation data may also provide a reference guide for the conservation and utilization of the BM miniature pig resource.
Effect of carbohydrases on growth performance, nutrient digestibility, blood profiles, and fecal microbiota in weanling pigs fed reduced energy diet
Authors: Ao Xiang , Zhang Song , Kim In Ho
Published: September 2019

This study was conducted to evaluate the effect of carbohydrases on growth performance, nutrient digestibility, blood profiles, and fecal microbiota in weanling pigs fed reduced energy diet. A total of 160 crossbred [(Yorkshire × Landrace) × Duroc)] weanling pigs with an initial body weight (BW) of 7.23 ± 1.08 kg were used in this 42 d trial. Pigs were randomly allocated in one of the following four dietary treatments: (1) CON, basal diet [net energy (NE) 2545 kcal kg−1]; (2) LE, low-energy diet (NE 2470 kcal kg−1); (3) LEC1, LE + 0.1% carbohydrase; and (4) LEC2, LE + 0.2% carbohydrase based on the sex and BW. There were eight replications (pens) per treatment with five pigs (two male and three female) per pen. During day 0–7, pigs fed with LE diet had lower (P < 0.05) average daily gain (ADG) and average daily feed intake than those fed with CON and LEC2 diets. LE group reduced (P < 0.05) ADG throughout the experiment compared with CON and LEC2 groups. LE group reduced (P < 0.05) the digestibility of dry matter, nitrogen, and gross energy compared with LEC2 diet. Taken together, LE diet caused detrimental effects on growth performance and nutrient digestibility in weanlings, whereas the addition of carbohydrases (0.2%) partially counteracted these negative effects.
Effect of heat treatment and heat treatment in combination with lignosulfonate on in situ rumen degradability of canola cake crude protein, lysine, and methionine
Authors: Micek Piotr , Słota Katarzyna , Górka Paweł
Published: September 2019

The aim of this study was to determine the effect of heat treatment alone or in combination with the addition of lignosulfonate (LSO3) on canola cake protein, lysine, and methionine degradation in the rumen. Cold-pressed canola cake was left untreated, heated at 90, 110, 130, or 150 °C, or processed with 5% of LSO3 (in dry matter) and then heated. Effective rumen degradability of crude protein (CP), lysine, and methionine was less for treated than untreated canola cake (P < 0.05) and decreased with increased temperature of heating, but particularly when canola cake was heated at 150 °C (quadratic, P < 0.01). In general, effective rumen degradability of CP, lysine, and methionine was less for canola cake heated at 130 °C in combination with LSO3 compared with canola cake heat treated only (quadratic × LSO3 interaction, P ≤ 0.07). Results of this study indicate that high temperature heating (130 °C or greater for 60 min) may be necessary to protect canola cake protein from degradation in the rumen, and the combination of heat treatment and LSO3 may be more effective in protecting canola cake protein, lysine, and methionine from degradation in the rumen than the use of heat treatment only.
Effect of flavor supplementation on growth performance, nutrient digestibility, blood profiles, and carcass quality in growing–finishing pigs
Authors: Ao Xiang , Lei Yan , Kim In Ho
Published: September 2019

This study was conducted to evaluate the effect of supplementation of different flavors (apple and anise) on growth performance, nutrient digestibility, blood profiles, and carcass quality in growing–finishing pigs. A total of 96 growing pigs [(Yorkshire × Landrace) × Duroc] with an average body weight (BW) of 28.2 ± 0.7 kg were randomly assigned to one of the following three treatments: (1) CON, basal diet; (2) APF, basal diet + 0.05% apple flavor; (3) ANF, basal diet + 0.05% anise flavor, according to their BW and sex in this 15 wk experiment. There were eight replications (pens) per treatment and four pigs per pen (two barrows and two gilts). During week 0–5, pigs fed ANF diets had greater (p < 0.05) average daily gain (ADG) and average daily feed intake than those fed CON and APF diets. Dietary ANF treatment increased (p < 0.05) ADG during 0–15 wk compared with CON treatment. At the end of 5 wk, the apparent total tract digestibility of nitrogen in ANF treatment was improved (p < 0.05) compared with that in CON treatment. Dietary treatments did not affect the studied traits of carcass and meat quality. The inclusion of anise flavor increased ADG, but apple flavor had no effect on growth performance in growing–finishing pigs.
Meat and sensory quality of major muscles from Angus, Charolais, and Angus crossbred steers with high and low residual feed intake
Authors: Jiu Zhiqiang , Roy Bimol C. , Das Chamali , Wismer Wendy V. , Juárez Manuel , Fitzsimmons Carolyn , Li Changxi , Plastow Graham , Aalhus Jennifer L. , Bruce Heather L.
Published: September 2019

Effects of residual feed intake (RFI) and genetic group on growth, carcass, and meat quality characteristics of bovine longissimus lumborum (LL), triceps brachii (TB), semimembranosus (SM), and gluteus medius (GM) muscles were investigated using 72 purebred Angus, purebred Charolais, and Angus crossbred steers (n = 24 per genetic group) classified as either high (inefficient) or low (efficient) RFI (n = 12 high and low RFI steers within genetic group). There was no RFI effect (P > 0.05) on growth, carcass, and meat quality measurements except high RFI steers had the highest dry matter intake (P < 0.05), and low RFI TB was rated as having reduced beef flavour intensity and sustained juiciness (P < 0.05). Purebred Angus and Charolais LL and GM had lower shear force values (P < 0.05) than Angus crossbreds and ageing reduced mean shear force values except in TB. For TB, SM, and GM, Angus crossbred steers had the highest mean beef flavour intensity scores, and Charolais SM and TB were less tender than those of Angus crossbred (P < 0.05). Overall, RFI did not influence most meat quality traits; therefore, low RFI animals may contribute to reducing feed costs or environmental impact without compromising meat quality and palatability.
Feedlot performance, carcass characteristics, and meat characteristics of lambs grown under silvopastoral systems
Authors: van Cleef F.O.S. , van Cleef E.H.C.B. , Longhini V.Z. , Nascimento T.S. , Ezequiel J.M.B. , Ruggieri A.C.
Published: September 2019

Crossbred lambs were grown under different production systems (unshaded, moderate shading, intense shading) and were submitted to a feedlot finishing period where the performance, efficiency, carcass characteristics, and meat characteristics were evaluated. The dry matter intake was similar among treatments as well as the daily gain and feed efficiency. Hot and cold carcass weights, their dressing percentages, initial and final carcass temperature and pH, as well as initial and final color of meat were unaffected by treatments. In conclusion, the silvopastoral system used during the growing phase neither improved feedlot performance, feed efficiency, nor carcass and meat characteristics of crossbred lambs.
Experimental investigation of the effect of skew angle on partially or fully submerged deck scour
Authors: Baduna Koçyiğit Müsteyde , Koçyiğit Önder , Akay Hüseyin , Demir Gülay
Published: September 2019

This paper presents the results of an experimental study investigating the effect of skew angle on clear-water contraction scour under a bridge deck at partially and fully submerged flow conditions. Two bridge deck models without a pier, one of which was located perpendicular to the flow while the other one was located with skewness of 15°, were used in the study. Forty experiments were performed for each deck model, 24 of which were under partially submerged and 16 were under fully submerged flow conditions. Analysis of the experimental data showed that as the discharge and approach flow depth increased, the maximum scour hole depth under the skewed deck model increased up to 25%–66% for fully submerged flow and 17%–57% for partially submerged flow conditions. Furthermore, the effect of skew angle significantly enlarged the width of the scour hole as you move along the skewed deck.
Taurine and cardiac disease: state of the art and perspectives
Authors: Bkaily Ghassan , Jazzar Ashley , Normand Alexandre , Simon Yanick , Al-Khoury Johny , Jacques Danielle
Published: September 2019

Taurine is a nonessential amino acid that has received much attention. Two organs, the heart and the brain, are known to produce their own taurine, but in very limited quantities. It is for this reason that supplementation with this amino acid is necessary. Today, taurine is present in almost all energy drinks. A very vast literature reported beneficial effects of taurine in hepatic dysfunction, gastrointestinal injury, kidney diseases, diabetes, and cardiovascular diseases. Most of its effects were attributed to its modulation of Ca2+homeostasis as well as to its antioxidant properties. In this review, we will focus on the current status of taurine modulation of the cardiovascular system and discuss future avenues for its use as a supplement therapy in a specific cardiovascular disease, namely hypertrophy, and heart failure.
Gamma-induced background in the KATRIN main spectrometer
Authors: Altenmüller K. , Arenz M. , Baek W.-J. , Beck M. , Beglarian A. , Behrens J. , Berlev A. , Besserer U. , Blaum K. , Block F. , Bobien S. , Bode T. , Bornschein B. , Bornschein L. , Bouquet H. , Brunst T. , Buzinsky N. , Chilingaryan S. , Choi W. Q. , Deffert M. , Doe P. J. , Dragoun O. , Drexlin G. , Dyba S. , Eitel K. , Ellinger E. , Engel R. , Enomoto S. , Erhard M. , Eversheim D. , Fedkevych M. , Formaggio J. A. , Fränkle F. M. , Franklin G. B. , Friedel F. , Fulst A. , Gil W. , Glück F. , Ureña A. Gonzalez , Grössle R. , Gumbsheimer R. , Hackenjos M. , Hannen V. , Harms F. , Haußmann N. , Heizmann F. , Helbing K. , Herz W. , Hickford S. , Hilk D. , Hillesheimer D. , Howe M. A. , Huber A. , Jansen A. , Karl C. , Kellerer J. , Kernert N. , Kippenbrock L. , Klein M. , Kopmann A. , Korzeczek M. , Kovalík A. , Krasch B. , Kraus A. , Kraus M. , Lasserre T. , Lebeda O. , Lehnert B. , Letnev J. , Lokhov A. , Machatschek M. , Marsteller A. , Martin E. L. , Mertens S. , Mirz S. , Monreal B. , Neumann H. , Niemes S. , Osipowicz A. , Otten E. , Parno D. S. , Pollithy A. , Poon A. W. P. , Priester F. , Ranitzsch P. C.-O. , Rest O. , Robertson R. G. H. , Rodenbeck C. , Röllig M. , Röttele C. , Ryšavý M. , Sack R. , Saenz A. , Schimpf L. , Schlösser K. , Schlösser M. , Schlüter L. , Schrank M. , Seitz-Moskaliuk H. , Sibille V. , Slezák M. , Steidl M. , Steinbrink N. , Sturm M. , Suchopar M. , Tcherniakhovski D. , Telle H. H. , Thorne L. A. , Thümmler T. , Titov N. , Tkachev I. , Trost N. , Valerius K. , Vénos D. , Vianden R. , Hernández A. P. Vizcaya , Weber M. , Weinheimer C. , Weiss C. , Welte S. , Wendel J. , Wilkerson J. F. , Wolf J. , Wüstling S. , Zadoroghny S. , Zeller G.
Published: September 2019

The KATRIN experiment aims to measure the effective electron antineutrino mass $$m_{\overline{\nu }_e}$$mν¯e with a sensitivity of $${0.2}\,{\hbox {eV}/\hbox {c}^2}$$0.2eV/c2 using a gaseous tritium source combined with the MAC-E filter technique. A low background rate is crucial to achieving the proposed sensitivity, and dedicated measurements have been performed to study possible sources of background electrons. In this work, we test the hypothesis that gamma radiation from external radioactive sources significantly increases the rate of background events created in the main spectrometer (MS) and observed in the focal-plane detector. Using detailed simulations of the gamma flux in the experimental hall, combined with a series of experimental tests that artificially increased or decreased the local gamma flux to the MS, we set an upper limit of $${0.006}\,{\hbox {count}/\hbox {s}}$$0.006count/s (90% C.L.) from this mechanism. Our results indicate the effectiveness of the electrostatic and magnetic shielding used to block secondary electrons emitted from the inner surface of the MS.
Quantum Turbulence in Quantum Gases
Authors: Madeira L. , Caracanhas M.A. , dos Santos F.E.A. , Bagnato V.S.
Published: September 2019

Turbulence is characterized by a large number of degrees of freedom, distributed over several length scales, that result in a disordered state of a fluid. The field of quantum turbulence deals with the manifestation of turbulence in quantum fluids, such as liquid helium and ultracold gases. We review, from both experimental and theoretical points of view, advances in quantum turbulence focusing on atomic Bose–Einstein condensates. We also explore the similarities and differences between quantum and classical turbulence. Last, we present challenges and possible directions for the field. We summarize questions that are being asked in recent works, which need to be answered in order to understand fundamental properties of quantum turbulence, and we provide some possible ways of investigating them.
Physical Models of Collective Cell Migration
Authors: Alert Ricard , Trepat Xavier
Published: September 2019

Collective cell migration is a key driver of embryonic development, wound healing, and some types of cancer invasion. Here, we provide a physical perspective of the mechanisms underlying collective cell migration. We begin with a catalog of the cell–cell and cell–substrate interactions that govern cell migration, which we classify into positional and orientational interactions. We then review the physical models that have been developed to explain how these interactions give rise to collective cellular movement. These models span the subcellular to the supracellular scales, and they include lattice models, phase-field models, active network models, particle models, and continuum models. For each type of model, we discuss its formulation, its limitations, and the main emergent phenomena that it has successfully explained. These phenomena include flocking and fluid–solid transitions, as well as wetting, fingering, and mechanical waves in spreading epithelial monolayers. We close by outlining remaining challenges and future directions in the physics of collective cell migration.
Targeting the Trafficking of Kidney Water Channels for Therapeutic Benefit
Authors: Cheung Pui W. , Bouley Richard , Brown Dennis
Published: September 2019

The ability to regulate water movement is vital for the survival of cells and organisms. In addition to passively crossing lipid bilayers by diffusion, water transport is also driven across cell membranes by osmotic gradients through aquaporin water channels. There are 13 aquaporins in human tissues, and of these, aquaporin-2 (AQP2) is the most highly regulated water channel in the kidney: The expression and trafficking of AQP2 respond to body volume status and plasma osmolality via the antidiuretic hormone, vasopressin (VP). Dysfunctional VP signaling in renal epithelial cells contributes to disorders of water balance, and research initially focused on regulating the major cAMP/PKA pathway to normalize urine concentrating ability. With the discovery of novel and more complex signaling networks that regulate AQP2 trafficking, promising therapeutic targets have since been identified. Several strategies based on data from preclinical studies may ultimately translate to the care of patients with defective water homeostasis.
Rethinking Food Reward
Authors: de Araujo Ivan E. , Schatzker Mark , Small Dana M.
Published: September 2019

The conscious perception of the hedonic sensory properties of caloric foods is commonly believed to guide our dietary choices. Current and traditional models implicate the consciously perceived hedonic qualities of food as driving overeating, whereas subliminal signals arising from the gut would curb our uncontrolled desire for calories. Here we review recent animal and human studies that support a markedly different model for food reward. These findings reveal in particular the existence of subcortical body-to-brain neural pathways linking gastrointestinal nutrient sensors to the brain's reward regions. Unexpectedly, consciously perceptible hedonic qualities appear to play a less relevant, and mostly transient, role in food reinforcement. In this model, gut-brain reward pathways bypass cranial taste and aroma sensory receptors and the cortical networks that give rise to flavor perception. They instead reinforce behaviors independently of the cognitive processes that support overt insights into the nature of our dietary decisions.
Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response
Authors: McGregor Grace H. , Campbell Andrew D. , Fey Sigrid K. , Tumanov Sergey , Sumpton David , Blanco Giovanny Rodriguez , Mackay Gillian , Nixon Colin , Vazquez Alexei , Sansom Owen J. , Kamphorst Jurre J.
Published: September 2019

Statins are widely prescribed inhibitors of the mevalonate pathway, acting to lower systemic cholesterol levels. The mevalonate pathway is critical for tumorigenesis and is frequently upregulated in cancer. Nonetheless, reported effects of statins on tumor progression are ambiguous, making it unclear whether statins, alone or in combination, can be used for chemotherapy. Here, using advanced mass spectrometry and isotope tracing, we showed that statins only modestly affected cancer cholesterol homeostasis. Instead, they significantly reduced synthesis and levels of another downstream product, the mitochondrial electron carrier coenzyme Q, both in cultured cancer cells and tumors. This compromised oxidative phosphorylation, causing severe oxidative stress. To compensate, cancer cells upregulated antioxidant metabolic pathways, including reductive carboxylation, proline synthesis, and cystine import. Targeting cystine import with an xCT transporter–lowering MEK inhibitor, in combination with statins, caused profound tumor cell death. Thus, statin-induced ROS production in cancer cells can be exploited in a combinatorial regimen.

Significance:

Cancer cells induce specific metabolic pathways to alleviate the increased oxidative stress caused by statin treatment, and targeting one of these pathways synergizes with statins to produce a robust antitumor response.

See related commentary by Cordes and Metallo, p. 151
Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti–PD-1 Resistance in Head and Neck Cancer
Authors: Zhou Liye , Mudianto Tenny , Ma Xiaojing , Riley Rachel , Uppaluri Ravindra
Published: September 2019

Purpose:

Anti–programmed death-1 (PD-1) receptor–based therapeutics improve survival in patients with recurrent head and neck squamous cell carcinoma (HNSCC), but many do not benefit due to a low response rate. Herein, we identified EZH2 as a therapeutic target that enhanced tumor cell antigen presentation and subsequently sensitized resistant tumors to anti–PD-1 therapy.

Experimental Design:

EZH2 regulation of antigen presentation was defined using EZH2 inhibitors (GSK126 and EPZ6438) in human and mouse HNSCC cell lines. Mechanistic dissection of EZH2 in regulation of antigen presentation was investigated using flow cytometry, qRT-PCR, ELISA, and chromatin-immunoprecipitation assays. EZH2-deficient cell lines were generated using CRISPR-CAS9. GSK126 and anti–PD-1–blocking antibody were used in testing combinatorial therapy in vivo.

Results:

EZH2 expression was negatively correlated with antigen-processing machinery pathway components in HNSCC data sets in The Cancer Genome Atlas. EZH2 inhibition resulted in significant upregulation of MHC class I expression in human and mouse human papillomavirus–negative HNSCC lines in vitro and in mouse models in vivo. Enhanced antigen presentation on the tumor cells by EZH2 inhibitors or CRISPR–mediated EZH2 deficiency increased antigen-specific CD8+ T-cell proliferation, IFNγ production, and tumor cell cytotoxicity. Mechanistically, EZH2 inhibition reduced the histone H3K27me3 modification on the β-2-microglobulin promoter. Finally, in an anti–PD-1–resistant model of HNSCC, tumor growth was suppressed with combination therapy.

Conclusions:

Our results demonstrated that targeting EZH2 enhanced antigen presentation and was able to circumvent anti–PD-1 resistance. Thus, combining EZH2 targeting with anti–PD-1 may increase therapeutic susceptibility in HNSCC.
DNA Methylation Profiling Identifies Distinct Clusters in Angiosarcomas
Authors: Weidema Marije E. , van de Geer Ellen , Koelsche Christian , Desar Ingrid M.E. , Kemmeren Patrick , Hillebrandt-Roeffen Melissa H.S. , Ho Vincent K.Y. , van der Graaf Winette T.A. , Versleijen-Jonkers Yvonne M.H. , von Deimling Andreas , Flucke Uta E.
Published: September 2019

Purpose:

DNA methylation profiling has previously uncovered biologically and clinically meaningful subgroups within many tumor types, but was not yet performed in angiosarcoma. Angiosarcoma is a rare sarcoma with very heterogeneous clinical presentations, which may be based on differences in biological background. In this exploratory study, DNA methylation profiling of 36 primary angiosarcoma samples from visceral, deep soft tissue, radiation-induced, and UV-induced localizations was performed.

Experimental Design:

Primary angiosarcoma formalin-fixed paraffin-embedded samples from visceral, soft tissue, radiation-induced, and UV-induced origin were collected from a nationwide search for angiosarcoma in the Netherlands. DNA was extracted for methylation profiling with the Illumina Infinium MethylationEPIC array. Quality control assessment and unsupervised hierarchical clustering were performed. Copy-number profiles were generated and analyzed for chromosomal stability. Clinical data were obtained from the Netherlands Cancer Registry.

Results:

DNA methylation profiling by unsupervised hierarchical clustering of 36 angiosarcoma samples (6 visceral, 5 soft tissue, 14 radiation-induced, 11 UV-induced) revealed two main clusters (A and B), which were divided into four subclusters. The clusters largely corresponded with clinical subtypes, showing enrichment of UV-induced cases in cluster A1 and radiation-induced cases in cluster A2. Visceral and soft tissue cases almost exclusively fell into cluster B. Cluster A showed significantly increased chromosomal instability and better overall survival (22 vs. 6 months, P = 0.046) compared with cluster B.

Conclusions:

In this novel methylation profiling study, we demonstrated for the first time four different angiosarcoma clusters. These clusters correlated with clinical subtype, overall survival, and chromosomal stability.
Quantitative High-Throughput Screening Using an Organotypic Model Identifies Compounds that Inhibit Ovarian Cancer Metastasis
Authors: Kenny Hilary A. , Lal-Nag Madhu , Shen Min , Kara Betul , Nahotko Dominik A. , Wroblewski Kristen , Fazal Sarah , Chen Siquan , Chiang Chun-Yi , Chen Yen-Ju , Brimacombe Kyle R. , Marugan Juan , Ferrer Marc , Lengyel Ernst
Published: September 2019

The tumor microenvironment (TME) is a key determinant of metastatic efficiency. We performed a quantitative high-throughput screen (qHTS) of diverse medicinal chemistry tractable scaffolds (44,420 compounds) and pharmacologically active small molecules (386 compounds) using a layered organotypic, robust assay representing the ovarian cancer metastatic TME. This 3D model contains primary human mesothelial cells, fibroblasts, and extracellular matrix, to which fluorescently labeled ovarian cancer cells are added. Initially, 100 compounds inhibiting ovarian cancer adhesion/invasion to the 3D model in a dose-dependent manner were identified. Of those, eight compounds were confirmed active in five high-grade serous ovarian cancer cell lines and were further validated in secondary in vitro and in vivo biological assays. Two tyrosine kinase inhibitors, PP-121 and milciclib, and a previously unreported compound, NCGC00117362, were selected because they had potency at 1 μmol/L in vitro. Specifically, NCGC00117362 and PP-121 inhibited ovarian cancer adhesion, invasion, and proliferation, whereas milciclib inhibited ovarian cancer invasion and proliferation. Using in situ kinase profiling and immunoblotting, we found that milciclib targeted Cdk2 and Cdk6, and PP-121 targeted mTOR. In vivo, all three compounds prevented ovarian cancer adhesion/invasion and metastasis, prolonged survival, and reduced omental tumor growth in an intervention study. To evaluate the clinical potential of NCGC00117362, structure–activity relationship studies were performed. Four close analogues of NCGC00117362 efficiently inhibited cancer aggressiveness in vitro and metastasis in vivo. Collectively, these data show that a complex 3D culture of the TME is effective in qHTS. The three compounds identified have promise as therapeutics for prevention and treatment of ovarian cancer metastasis.
Modulating TAK1 Expression Inhibits YAP and TAZ Oncogenic Functions in Pancreatic Cancer
Authors: Santoro Raffaela , Zanotto Marco , Simionato Francesca , Zecchetto Camilla , Merz Valeria , Cavallini Chiara , Piro Geny , Sabbadini Fabio , Boschi Federico , Scarpa Aldo , Melisi Davide
Published: September 2019

YAP and TAZ are central determinants of malignancy; however, their functions remain still undruggable. We identified TGFβ-activated kinase 1 (TAK1) as a central hub integrating the most relevant signals sustaining pancreatic cancer aggressiveness and chemoresistance. Glycogen synthase kinase (GSK)3 is known to stabilize TAK1, and its inhibition causes a reduction in TAK1 levels. Here, we hypothesized that TAK1 could sustain YAP/TAZ program, and thus, modulation of TAK1 expression through the inhibition of GSK3 could impair YAP/TAZ functions in pancreatic cancer.

Differentially expressed transcripts between pancreatic cancer cells expressing scramble or TAK1-specific shRNA were annotated for functional interrelatedness by ingenuity pathway analysis. TAK1 expression was modulated by using different GSK3 inhibitors, including LY2090314. In vivo activity of LY2090314 alone or in combination with nab-paclitaxel was evaluated in an orthotopic nude mouse model.

Differential gene expression profiling revealed significant association of TAK1 expression with HIPPO and ubiquitination pathways. We measured a significant downregulation of YAP/TAZ and their regulated genes in shTAK1 cells. TAK1 prevented YAP/TAZ proteasomal degradation in a kinase independent manner, through a complex with TRAF6, thereby fostering their K63-ubiquitination versus K48-ubiquitination. Pharmacologic modulation of TAK1 by using GSK3 inhibitors significantly decreased YAP/TAZ levels and suppressed their target genes and oncogenic functions. In vivo, LY2090314 plus nab-paclitaxel significantly prolonged mice survival duration.

Our study demonstrates a unique role for TAK1 in controlling YAP/TAZ in pancreatic cancer. LY2090314 is a novel agent that warrants further clinical development in combination with nab-paclitaxel for the treatment of pancreatic cancer.