bluuebunny/crossref_metadata_2025 huggingface dataset:
Neisseria gonorrhoeae uses cellular proteins CXCL10 and IL8 to enhance HIV‐1 transmission across cervical mucosa
Authors: Sanyal Anwesha , Shen Chengli , Ding Ming , Reinhart Todd A. , Chen Yue , Sankapal Soni , Gupta Phalguni
Published: March 2019

Problem

Neisseria gonorrhoeae (NG) infection has been shown to increase sexual transmission of HIV‐1. However, the mechanism of NG‐induced enhanced HIV‐1 transmission is unknown.

Methods

(a) The cervical tissues were exposed to NG, and cytokine induction was monitored by measuring cytokine proteins in culture supernatants and cytokine mRNAs in tissues. (b) Transcription and replication of HIV‐1 in TZM‐bl, U1, and ACH2 cells were measured by Beta‐Gal activity and p24 proteins in the supernatant, respectively. (c) HIV‐1 transmission was assayed in an organ culture system by measuring transmitted HIV‐1 in supernatant and HIV‐1 gag mRNA in the tissues. (d) Transcriptome analysis was done using second generation sequencing.

Results

(a) NG induced membrane ruffling of epithelial layer, caused migration of CD3+ cells to the intraepithelial region, and induced high levels of inflammatory cytokines IL‐1β and TNF‐α. (b) NG‐induced supernatants (NGIS) increased HIV‐1 transcription, induced HIV‐1 from latently infected cells, and increased transmission of HIV‐1 across cervical mucosa. (c) Transcriptome analysis of the epithelial layer of the tissues exposed to NG, and HIV‐1 showed significant upregulation of CXCL10 and IL8. IL‐1β increased the induction of CXCL10 and IL‐8 expression in cervical mucosa with a concomitant increase in HIV‐1 transmission.

Conclusion

We present a model in which IL‐1β produced from cervical epithelium during NG exposure increases CXCL10 and IL8 in epithelia. This in turn causes upon HIV‐1 infection, the migration of HIV‐1 target cells toward the subepithelium, resulting in increased HIV‐1 transcription in the sub‐mucosa and subsequent enhancement of transmission across cervical mucosa.
The role and mechanism of vitamin D‐mediated regulation of Treg/Th17 balance in recurrent pregnancy loss
Authors: Ji Jinlu , Zhai Hui , Zhou Hui , Song Su , Mor Gil , Liao Aihua
Published: March 2019

Problem

Vitamin D has a pivotal role in regulating immune responses in women with recurrent pregnancy loss (RPL), but the underlying mechanism has not been completely clarified. This study aimed to determine the correlation between vitamin D and Treg/Th17 and the effects of vitamin D supplementation on Treg/Th17 balance in RPL patients.

Methods of study

The level of vitamin D was determined in women with normal pregnancy and RPL by electrochemiluminescence. The percentages of CD4+Foxp3+ Treg, CD4+IL‐17+ Th17, and CD4+Foxp3+IL‐17+ T cells were determined by flow cytometry before and after vitamin D supplementation. Changes about Treg/Th17 balance after culturing with active vitamin D in vitro were determined. Vitamin D metabolic activity of peripheral blood mononuclear cells was also detected by RT‐PCR.

Results

Compared with normal pregnancy, both the level of vitamin D and the Treg/Th17 ratio were significantly decreased in women with RPL. There was a positive correlation between the level of vitamin D and the Treg/Th17 ratio in the RPL group. Within the RPL group, those who received 2 months of vitamin D supplementation showed a significantly increased Treg/Th17 ratio compared with those without vitamin D supplementation. In vitro analysis showed that adding different concentrations of active vitamin D increased the Treg/Th17 ratio, also the mRNA levels of the vitamin D receptor and the metabolic enzyme CYP24A1 increased significantly.

Conclusion

The occurrence of RPL may be related to vitamin D insufficiency and Treg/Th17 imbalance. The Treg/Th17 imbalance seen in women with RPL can be restored by vitamin D supplementation both in vivo and in vitro. The effects of vitamin D on the immune regulation of RPL indicate that vitamin D might be used as an alternative therapy in the future.
Antimicrobial susceptibility of Neisseria gonorrhoeae isolates and treatment of gonorrhoea patients in Ternopil and Dnipropetrovsk regions of Ukraine, 2013–2018
Authors: Boiko Iryna , Golparian Daniel , Krynytska Inna , Bezkorovaina Halyna , Frankenberg Arkadii , Onuchyna Margarita , Jacobsson Susanne , Unemo Magnus
Published: March 2019

Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major public health concern globally. However, recent gonococcal AMR data from Eastern Europe are extremely limited and no AMR data for strains spreading in Ukraine have ever been internationally published. We investigated the AMR of N. gonorrhoeae isolates in two regions of Ukraine (Ternopil 2013–2018, Dnipropetrovsk 2013–2014), and, where information was available, the treatment administered to the corresponding gonorrhoea patients. Determination of minimum inhibitory concentration (MIC) of eight antimicrobials was performed using Etest and resistance breakpoints from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were applied. Overall, 9.3% of the examined 150 isolates were resistant to ciprofloxacin, 6.0% to tetracycline, 2.0% to azithromycin, and 0.7% to benzylpenicillin. No isolates were resistant to ceftriaxone, cefixime, spectinomycin, or gentamicin. However, one (0.7%) isolate showed a MIC value of 0.125 mg/L for both ceftriaxone and cefixime, i.e., bordering resistance. Eighty‐eight (67.2%) of 131 patients were administered dual therapy (ceftriaxone 1 g plus doxycycline/clarithromycin/azithromycin/ofloxacin) and 22 (16.8%) ceftriaxone 1 g monotherapy. Worryingly, 21 (16.0%) patients received monotherapy with clarithromycin/doxycycline/azithromycin/ofloxacin/benzylpenicillin. In conclusion, the antimicrobial susceptibility of gonococcal strains spreading in Ternopil and Dnipropetrovsk, Ukraine during 2013–2018 was high. Low levels of resistance to ciprofloxacin, tetracycline, azithromycin, and benzylpenicillin were found, but no resistance to the internationally recommended ceftriaxone, cefixime, or spectinomycin. Ceftriaxone 1 g should remain as empiric first‐line treatment, in dual therapy with azithromycin or doxycycline or in monotherapy. Continued and expanded gonococcal AMR surveillance in Ukraine is essential to monitor the susceptibility to particularly extended‐spectrum cephalosporins, azithromycin and doxycycline.
A dedicated high‐quality service for the management of patients with an inherited risk of colorectal cancer
Authors: Adams L. K. , Qiu S. , Hunt A. K. , Monahan K. J.
Published: March 2019

Aim

To demonstrate the quality improvement associated with the implementation of a specialist family history of bowel cancer service in secondary care.

Method

The following outcomes were assessed: (1) adherence to the British Society of Gastroenterology (BSG) guidelines for colonoscopic surveillance of individuals with a family history of colorectal cancer (CRC); (2) adherence to the revised Bethesda criteria for the identification of CRC patients with suspected Lynch syndrome; (3) identification of inherited syndromes with increased CRC risk; and (4) colonoscopic adenoma detection rate. Data were collected for a 21‐month period before and after the establishment of this service for all patients who underwent colonoscopic surveillance for a family history of CRC and all patients newly diagnosed with CRC. Analyses compared the number of colonoscopies performed that were not indicated by BSG guidelines, the average number of years early that patients were screened, the adenoma detection rate and the rate of tumour testing for mismatch repair genes before and after the implementation of the service.

Results

Following the establishment of the service there was a reduction in the number of colonoscopies not indicated by BSG guidelines (39.6% before and 5.8% after, P < 0.001, chi‐square test) and surveillance colonoscopy took place at a more appropriate age (10.6 years too early before and 5.9 years early after, P = 0.01, t‐test). There was an increased adenoma detection rate (17% before and 31.9% after, P < 0.01, chi‐square test) and increased tumour MMR testing (3.4% before and 91.8% after, P < 0.01, chi‐square test).

Conclusion

The introduction of a family history of bowel cancer service results in improved patient care through improved adherence to guidelines for colonoscopic surveillance and increased cancer detection rates.
Donor‐derived infections: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice
Authors: Wolfe Cameron R. , Ison Michael G. ,   the AST Infectious Diseases Community of Practice
Published: March 2019

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation will review the current state of the art of donor‐derived infections. Specifically, the guideline will summarize standardized definitions and approaches to defining imputability, updated data on the epidemiology of donor‐derived infections, and approaches to risk mitigation against transmission of infections. This update will additionally provide guidance on the use of HIV+ donors in HIV+ recipients, the use of HCV‐viremic donors in non‐viremic recipients, donors with endemic infections, and donors with bacteremia, meningitis, and encephalitis. Lastly, the guidance will summarize an approach to recipients with a suspected donor‐derived infection.
Landscape genomics to the rescue of a tropical bee threatened by habitat loss and climate change
Authors: Jaffé Rodolfo , Veiga Jamille C. , Pope Nathaniel S. , Lanes Éder C. M. , Carvalho Carolina S. , Alves Ronnie , Andrade Sónia C. S. , Arias Maria C. , Bonatti Vanessa , Carvalho Airton T. , de Castro Marina S. , Contrera Felipe A. L. , Francoy Tiago M. , Freitas Breno M. , Giannini Tereza C. , Hrncir Michael , Martins Celso F. , Oliveira Guilherme , Saraiva Antonio M. , Souza Bruno A. , Imperatriz‐Fonseca Vera L.
Published: March 2019

Habitat degradation and climate change are currently threatening wild pollinators, compromising their ability to provide pollination services to wild and cultivated plants. Landscape genomics offers powerful tools to assess the influence of landscape modifications on genetic diversity and functional connectivity, and to identify adaptations to local environmental conditions that could facilitate future bee survival. Here, we assessed range‐wide patterns of genetic structure, genetic diversity, gene flow, and local adaptation in the stingless bee Melipona subnitida, a tropical pollinator of key biological and economic importance inhabiting one of the driest and hottest regions of South America. Our results reveal four genetic clusters across the species’ full distribution range. All populations were found to be under a mutation–drift equilibrium, and genetic diversity was not influenced by the amount of reminiscent natural habitats. However, genetic relatedness was spatially autocorrelated and isolation by landscape resistance explained range‐wide relatedness patterns better than isolation by geographic distance, contradicting earlier findings for stingless bees. Specifically, gene flow was enhanced by increased thermal stability, higher forest cover, lower elevations, and less corrugated terrains. Finally, we detected genomic signatures of adaptation to temperature, precipitation, and forest cover, spatially distributed in latitudinal and altitudinal patterns. Taken together, our findings shed important light on the life history of M. subnitida and highlight the role of regions with large thermal fluctuations, deforested areas, and mountain ranges as dispersal barriers. Conservation actions such as restricting long‐distance colony transportation, preserving local adaptations, and improving the connectivity between highlands and lowlands are likely to assure future pollination services.
Imiquimod‐induced skin inflammation is relieved by knockdown of sodium channel Nax
Authors: Zhao Jingling , Xie Ping , Galiano Robert D. , Qi Shaohai , Mao Renxiang , Mustoe Thomas A. , Hong Seok Jong
Published: March 2019

Nax is an atypical sodium channel that mediates inflammatory pathways in pathological conditions of the skin. In this study, we developed a skin inflammation model in the rabbit ear through application of imiquimod (IMQ). Knockdown of Nax using RNAi attenuated IMQ‐induced skin inflammation, including skin erythema, scaling and papule formation. Histologic analysis showed that thickening and insufficient differentiation of the epidermis found in psoriasis‐like skin were normalized by administration of Nax‐RNAi. Excessive infiltration of inflammatory cells found in inflammatory lesions, such as mast cells, eosinophils, neutrophils, T cells and macrophages, was reduced by Nax‐RNAi. Expression of S100A9, which is a downstream gene of Nax and a mediator of inflammation, was decreased by Nax‐RNAi. Our results demonstrated that knockdown of Nax ameliorated IMQ‐induced psoriasis‐like skin inflammation in vivo. Thus, targeting of Nax may represent a potential therapeutic option for the treatment of psoriasis.
Treatment with either COX‐2 inhibitor or 5‐LOX inhibitor causes no compensation between COX‐2 pathway and 5‐LOX pathway in chronic aluminum overload‐induced liver injury in rats
Authors: Xia Hui , He Qin , Wang Hong , Wang Yongming , Yang Yang , Li Yuke , Zhang Jiahua , Chen Zhihao , Yang Junqing
Published: March 2019

This study was designed to observe the compensation between cyclooxygenase‐2 pathway and 5‐lipoxygenase pathway in chronic aluminum overload‐induced liver injury rats. A rat hepatic injury model of chronic aluminum injury was established by the intragastric administration of aluminum gluconate (Al3 + 200 mg/kg per day, 5 days a week for 20 weeks). The COX‐2 inhibitor [meloxicam (1 mg/kg)] and 5‐LOX inhibitor [caffeic acid (30 mg/kg)] were intragastrically administered 1 h after aluminum administration. The histopathology was detected by hematoxylin‐eosin staining. A series of biochemical indicators were measured with biochemistry assay or ELISAs. The expressions of COX‐2 and 5‐LOX were measured by immunohistochemistry. Our experimental results showed that aluminum overload caused a significant damage to the liver and also significantly increased the expressions of COX‐2, 5‐LOX and the levels of inflammation and oxidative stress. The administration of meloxicam and caffeic acid significantly protected livers against histopathological injury, significantly decreased plasma ALT, AST, and ALP levels, significantly decreased TNF‐α, IL‐6, IL‐1β levels, and oxidative stress. However, the administration of caffeic acid did not significantly increase the expression of COX‐2 compared with the model group. On the other hand, the administration of meloxicam also did not significantly increase the expression of 5‐LOX compared with the model group. Our results indicate that there is no compensation between COX‐2 pathway and 5‐LOX pathway by inhibiting either COX‐2 or 5‐LOX in chronic aluminum overload‐induced liver injury rat.
The structure and proximity mechanism of formal innovation networks: Evidence from Shanghai high‐tech ITISAs
Authors: Cao Xianzhong , Zeng Gang , Ye Lei
Published: March 2019

The discussion on innovation networks of patents or papers has attracted many economic geographers; however, the Industrial Technology Innovation Strategy Alliance (ITISA) has been ignored, although it is also an important innovation form of firms, and the formation mechanism of alliance innovation networks is unclear. This study is based on the data of Shanghai high‐tech ITISAs between 2010 and 2015, and employs the methods of social networks and negative binomial regression to analyse the actor structure, spatial structure, and proximity mechanism of innovation networks of Shanghai high‐tech ITISAs. Results highlight the following: (a) Firms comprise the largest number of actors in alliance innovation networks, and universities, research institutions, and industry associations also play some roles. (b) The local and rooted characteristics of the innovation networks of ITISAs are obvious. The spatial distribution of innovation partners is mainly in Shanghai, and a few innovation actors are located in neighbouring cities, such as Suzhou, Hangzhou, and Ningbo in the Yangtze River Delta Urban Agglomeration. (c) Proximity significantly promotes the formation of innovation networks in an ITISA and contributes to the improvement of innovation ability, and organizational proximity plays a greater role than geographical proximity or cognitive proximity.
Deleuze and Guattari's Absent Analysis of Patriarchy
Authors: Thornton Edward
Published: March 2019

Feminist philosophy has offered mixed opinions on the collaborative projects of Gilles Deleuze and Félix Guattari. But although there has been much discussion of the political expediency of what Deleuze and Guattari do say about sexual difference, this article will outline what is absent fromAnti‐OedipusandA Thousand Plateaus(the two volumes comprisingCapitalism and Schizophrenia). Specifically, I will argue that though Deleuze and Guattari offer a historical account of a range of power structures—most notably capitalism, but also despotism, fascism, and authoritarianism—they give no such account of the development of patriarchy. Secondarily, this article will argue that Deleuze and Guattari's analysis of contemporary power relations could be improved by adding an accompanying analysis of the institution of patriarchy. After offering a detailed account of the technical vocabulary used by Deleuze and Guattari for the analysis of political institutions, I will argue that what their work requires is an account of how patriarchy is historically produced by an “abstract machine” of masculinity. This article will finish with some suggestions for the way that such an account could be given via an analysis of the abstract machine ofphallusization.
Microwave dielectric properties and thermally stimulated depolarization of Al‐doped Ba4(Sm,Nd)9.33Ti18O54 ceramics
Authors: Guo Weijia , Zhang Jie , Luo Yu , Yue Zhenxing , Li Longtu
Published: March 2019

Ba4(Sm0.15Nd0.85)9.33Ti18‐zAl3z/4O54 (BSNT‐zAl, 0.0 ≤ z ≤ 2.5) ceramics were prepared via a solid‐state reaction, and the effects of Al doping on the microwave dielectric properties and defect behavior of the title compound were studied. X‐ray diffraction (XRD) analysis and scanning electron microscopy (SEM) photographs suggested that Al ions successfully entered the lattice to form tungsten‐bronze‐like solid solutions. With a small amount of Al substitution, the relative dielectric constant (εr), and the temperature coefficient of resonant frequency (τf) values decreased, whereas the quality factor (Q × f) substantially increased by approximately 50%. The defect‐related extrinsic dielectric loss was clarified via the thermally stimulated depolarization current (TSDC) technique. With Al doping, the TSDC relaxation of across‐grain‐boundary oxygen vacancies () vanished, whereas that of defect dipoles () appeared at relatively low temperatures. Therefore, in the BSNT‐zAl ceramics, oxygen vacancies were more inclined to interconnect with to form defect dipoles. This could reduce the activity of and account for the notable improvement in the Q × f values. In particular, the excellent characteristics of εr = 67.33, Q × f = 16 530 GHz, and τf = +0.87 ppm/°C were achieved in the specimens with z = 1.5 sintered at 1350°C for 4 hours.
Wnt and RUNX2 mediate cartilage breakdown by osteoarthritis synovial fibroblast‐derived ADAMTS‐7 and ‐12
Authors: Pérez‐García Selene , Carrión Mar , Villanueva‐Romero Raúl , Hermida‐Gómez Tamara , Fernández‐Moreno Mercedes , Mellado Mario , Blanco Francisco J. , Juarranz Yasmina , Gomariz Rosa P.
Published: March 2019

Failure of therapeutic approaches for the treatment of osteoarthritis (OA) based on the inhibition of metalloproteinases, might be because of their constitutive expression in homeostasis, together with their network complexity. The knowledge of this network would contribute to selective target pathological conditions. In this sense, blockade of mediators produced by neighbouring joint cells, such as synovial fibroblasts (SF), would prevent cartilage damage. Thus, we studied the contribution of ADAMTS‐7 and ‐12 from SF to cartilage oligomeric matrix protein (COMP) degradation, and the signalling pathways involved in their expression. We report for the first time in SF, the involvement of ERK‐Runx2 axis and Wnt/β‐catenin signalling in ADAMTS‐12 and ADAMTS‐7 expressions, respectively, with the subsequent consequences in COMP degradation from cartilage extracellular matrix. After stimulation with IL‐1β or fibronectin fragments, we showed that ERK inhibition decreased Runx2 activation and ADAMTS‐12 expression in OA‐SF, also reducing Fn‐fs‐induced COMP degradation. Blockage of Wnt signalling by DKK1 reduced ADAMTS‐7 and COMP degradation in OA‐SF as well. In addition, Wnt7B expression was induced by IL‐1β and by itself, also increasing ADAMTS‐7. Our results could contribute to the development of disease‐modifying OA drugs targeting ADAMTS‐7 and ‐12 for the prevention of extracellular matrix components degradation like COMP.
Longer life span is associated with elevated immune activity in a seasonally polyphenic butterfly
Authors: Freitak Dalial , Tammaru Toomas , Sandre Siiri‐Lii , Meister Hendrik , Esperk Toomas
Published: March 2019

Seasonal polyphenism constitutes a specific type of phenotypic plasticity in which short‐lived organisms produce different phenotypes in different times of the year. Seasonal generations of such species frequently differ in their overall lifespan and in the values of traits closely related to fitness. Seasonal polyphenisms provide thus excellent, albeit underused model systems for studying trade‐offs between life‐history traits. Here, we compare immunological parameters between the two generations of the European map butterfly (Araschnia levana), a well‐known example of a seasonally polyphenic species. To reveal possible costs of immune defence, we also examine the concurrent differences in several life‐history traits. Both in laboratory experiments and in the field, last instar larvae heading towards the diapause (overwintering) had higher levels of both phenoloxidase (PO) activity and lytic activity than directly developing individuals. These results suggest that individuals from the diapausing generation with much longer juvenile (pupal) period invest more in their immune system than those from the short‐living directly developing generation. The revealed negative correlation between pupal mass and PO activity may be one of the reasons why, in this species, the diapausing generation has a smaller body size than the directly developing generation. Immunological parameters may thus well mediate trade‐offs between body size‐related traits.
Economic injury level and crop loss assessment for Tuta absoluta (Lepidoptera: Gelechiidae) on different tomato cultivars
Authors: Ghaderi Saeedeh , Fathipour Yaghoub , Asgari Shahriar , Reddy Gadi V. P.
Published: March 2019

Specifying the relationship between pests and their host plants in terms of damage is one of the basic concepts of integrated pest management (IPM) programmes. The crop loss and economic injury level (EIL) of Tuta absoluta (Lepidoptera: Gelechiidae) were determined on different tomato cultivars using gain threshold (field experiment) and regression (semi‐field experiment) methods. By assessing the crop loss in 2015 and 2016, four out of seven infested tomato cultivars had a significant yield loss in terms of weight of total fruits versus the control under the open‐field conditions. However, the total number of tomato cultivars had no significant difference to control treatment. The semi‐field experiment included six treatments (0, 2, 4, 6, 8 and 10 gravid females/plant) and examined two tomato cultivars. The tomato cages with between 6 and 10 gravid females/plant showed the highest number and weight of damaged fruits. Based on pesticide control costs, the market value of tomato and the control efficacy, we determined the EIL for T. absoluta. In the field experiment, the EIL value for T. absoluta on “Petomech,” “Cal JN3,” “Rio Grande” and “Early Urbana Y” cultivars was 4.15, 4.47, 4.70 and 5.04 larvae per plant, respectively. Based on regression equations, we calculated the EIL values for T. absoluta on “Cal JN3” and “Early Urbana Y” to be 4.75 and 5.44 larvae/plant, respectively. Crop loss assessment and EIL are necessary components of cost‐effective IPM programs and can be effective tools for making decisions about the application of pesticides against T. absoluta.
Depressive Symptoms and Total Healthcare Costs: Roles of Functional Limitations and Multimorbidity
Authors: Schousboe John T. , Vo Tien N. , Kats Allyson M. , Langsetmo Lisa , Diem Susan J. , Taylor Brent C. , Strotmeyer Elsa S. , Ensrud Kristine E.
Published: March 2019

OBJECTIVES

Depressive symptoms can be both a cause and a consequence of functional limitations and medical conditions. Our objectives were to determine the association of depressive symptoms with subsequent total healthcare costs in older women after accounting for functional limitations and multimorbidity.

DESIGN

Prospective cohort study (Study of Osteoporotic Fractures [SOF]).

SETTING

Four US sites.

PARTICIPANTS

A total of 2508 community‐dwelling women (mean age = 79.4 years) participating in the SOF year 10 (Y10) examination linked with their Medicare claims data.

MEASUREMENTS

At Y10, depressive symptoms were measured using the 15‐item Geriatric Depression Scale (GDS) and functional limitations were assessed by number (range = 0‐5) of impairments in performing instrumental activities of daily living. Multimorbidity was ascertained by the Elixhauser method using claims data for the 12 months preceding the Y10 examination. Total direct healthcare costs, outpatient costs, acute hospital stays, and skilled nursing facility during the 12 months following the Y10 examination were ascertained from claims data.

RESULTS

Annualized mean (SD) total healthcare costs were $4654 ($9075) in those with little or no depressive symptoms (GDS score = 0‐1), $7871 ($14 534) in those with mild depressive symptoms (GDS score = 2‐5), and $9010 ($15 578) in those with moderate to severe depressive symptoms (GDS score = 6 or more). After adjustment for age, site, self‐reported functional limitations, and multimorbidity, the magnitudes of these incremental costs were partially attenuated (cost ratio = 1.34 [95% confidence interval {CI} = 1.14‐1.59] for those with mild depressive symptoms, and cost ratio = 1.29 [95% CI = 0.99‐1.69] for those with moderate to severe depressive symptoms vs women with little or no depressive symptoms).

CONCLUSION

Depressive symptoms were associated with higher subsequent healthcare costs attributable, in part, to greater functional limitations and multimorbidity among those with symptoms. Importantly, even mild depressive symptoms were associated with higher healthcare costs. J Am Geriatr Soc 67:1596–1603, 2019
Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance
Authors: Fouassier Laura , Marzioni Marco , Afonso Marta B. , Dooley Steven , Gaston Kevin , Giannelli Gianluigi , Rodrigues Cecilia M. P. , Lozano Elisa , Mancarella Serena , Segatto Oreste , Vaquero Javier , Marin Jose J. G. , Coulouarn Cédric
Published: March 2019

Cholangiocarcinoma (CCA) is a deadly disease. While surgery may attain cure in a minor fraction of cases, therapeutic options in either the adjuvant or advanced setting are limited. The possibility of advancing the efficacy of therapeutic approaches to CCA relies on understanding its molecular pathogenesis and developing rational therapies aimed at interfering with oncogenic signalling networks that drive and sustain cholangiocarcinogenesis. These efforts are complicated by the intricate biology of CCA, which integrates not only the driving force of tumour cell‐intrinsic alterations at the genetic and epigenetic level but also pro‐tumorigenic cues conveyed to CCA cells by different cell types present in the rich tumour stroma. Herein, we review our current understanding of the mechanistic bases underpinning the activation of major oncogenic pathways causative of CCA pathogenesis. We subsequently discuss how this knowledge is being exploited to implement rationale‐based and genotype‐matched therapeutic approaches that predictably will radically transform CCA clinical management in the next decade. We conclude by highlighting the mechanisms of therapeutic resistance in CCA and reviewing innovative approaches to combat resistance at the preclinical and clinical level.
Maternal iron intake during pregnancy and the risk of small for gestational age
Authors: Martínez‐Galiano Juan Miguel , Amezcua‐Prieto Carmen , Cano‐Ibañez Naomi , Salcedo‐Bellido Inmaculada , Bueno‐Cavanillas Aurora , Delgado‐Rodriguez Miguel
Published: March 2019

Studies of iron and its association with the risk of small for gestational age (SGA) show inconsistent results. Consuming iron supplements during pregnancy is controversial because of possible risks. This study assessed the association between iron intake and the risk of having an SGA newborn and whether iron intake is associated with gestational diabetes. A case–control study of 518 pairs of Spanish women who were pregnant and attending five hospitals was conducted. Groups were matched 1:1 for age (±2 years) and hospital. Cases were women with an SGA newborn at delivery. Controls were women with normal‐sized newborns at delivery. Data were gathered on demographic characteristics, socio‐economic status, adverse habits (like smoking), and diet. A 137‐item food frequency questionnaire was completed. Iron intakes were categorized in quintiles (Q1–Q5). Crude odds ratios (ORs) and adjusted ORs (aORs) with 95% confidence intervals (CIs) were estimated by conditional logistic regression. No significant relationship was found between dietary iron intake and SGA. A protective association was found for women receiving iron supplementation >40 mg/day and SGA versus women not taking supplements (aOR = 0.64, 95% CI [0.42, 0.99]). This association was identified in mothers both with (aOR = 0.57, 95% CI [0.40, 0.81]) and without (aOR = 0.64, 95% CI [0.64, 0.97]) anaemia. In women in the control group without anaemia, iron supplementation >40 mg/day was positively associated with gestational diabetes (aOR = 6.32, 95% CI [1.97, 20.23]). Iron supplementation in pregnancy may prevent SGA independently of existing anaemia but may also increase the risk of gestational diabetes.
Gestational weight gain and newborn anthropometric outcomes in rural Bangladesh
Authors: Kac Gilberto , Arnold Charles D. , Matias Susana L. , Mridha Malay K. , Dewey Kathryn G.
Published: March 2019

Low gestational weight gain (GWG) is a known predictor of fetal growth restriction in higher income countries, but there is little information on this association in lower income countries. Our objective is to describe the association between GWG and birth outcomes among pregnant women in rural Bangladesh. Pregnant women were identified in a community‐based programme and enrolled into the study at an average of 13 weeks' gestation (n = 4,011). Maternal weight and height were measured at enrolment, maternal weight was measured at 36 weeks' gestation, and newborns were measured after birth. Rate of GWG (g/weeks) was calculated, and women were categorized as having adequate or inadequate GWG (Institute of Medicine recommendations). Newborn anthropometric outcomes included weight‐for‐age z score (WAZ), length‐for‐age z score (LAZ), head‐circumference‐for‐age z score (HCZ), body mass index (BMI)‐for‐age z score (BMIZ), low birthweight (LBW < 2,500 g), WAZ < −2, LAZ < −2, HCZ < −2, BMIZ < −2, and small for gestational age (SGA: <10th percentile). Multivariate models were adjusted for confounders. Only 26% of the 2,562 women in these analyses had adequate GWG. Compared with newborns of women with inadequate GWG, infants of women with adequate GWG had a lower risk of adverse anthropometric outcomes (relative risk [95% confidence interval]: LBW = 0.68 [0.59, 0.80], LAZ < −2 = 0.64 [0.51, 0.80], HCZ < −2 = 0.75 [0.60, 0.93], BMIZ < −2 = 0.70 [0.59, 0.83], and SGA = 0.80 [0.73, 0.86]), but there was no significant difference in mean (SE) duration of gestation, 39.7 (0.08) versus 39.7 (0.05) weeks. In this population, GWG rate is a strong predictor of newborn anthropometric outcomes, but not duration of gestation.
Detachment of the RNA degradosome from the inner membrane of Escherichia coli results in a global slowdown of mRNA degradation, proteolysis of RNase E and increased turnover of ribosome‐free transcripts
Authors: Hadjeras Lydia , Poljak Leonora , Bouvier Marie , Morin‐Ogier Quentin , Canal Isabelle , Cocaign‐Bousquet Muriel , Girbal Laurence , Carpousis Agamemnon J.
Published: March 2019

The reason for RNase E attachment to the inner membrane is largely unknown. To understand the cell biology of RNA degradation, we have characterized a strain expressing RNase E lacking the membrane attachment site (cytoplasmic RNase E). Genome‐wide data show a global slowdown in mRNA degradation. There is no correlation between mRNA stabilization and the function or cellular location of encoded proteins. The activity of cRNase E is comparable to the wild‐type enzyme in vitro, but the mutant protein is unstable in vivo. Autoregulation of cRNase E synthesis compensates for protein instability. cRNase E associates with other proteins to assemble a cytoplasmic RNA degradosome. CsrB/C sRNAs, whose stability is regulated by membrane‐associated CsrD, are stabilized. Membrane attachment of RNase E is thus necessary for CsrB/C turnover. In contrast to mRNA stability, ribosome‐free transcripts are sensitive to inactivation by cRNase E. Our results show that effects on RNA degradation are not due to the differences in the activity or level of cRNase E, or failure to assemble the RNA degradosome. We propose that membrane attachment is necessary for RNase E stability, functional interactions with membrane‐associated regulatory factors and protection of ribosome‐free transcripts from premature interactions with RNase E in the nucleoid.
Efficacy of the current of injury in envisaging the dislodgement of leads implanted in the right atrial septum or the right ventricular septum
Authors: Yoshiyama Tomotaka , Shimeno Kenji , Matsuo Masanori , Matsumoto Ryo , Matsumura Yoshiki , Abe Yukio , Naruko Takahiko , Yoshiyama Minoru
Published: March 2019

Background

The implantation of leads in the right atrial septum (RAS) or the right ventricular septum (RVS) is technically challenging, and dislodgement occurs occasionally. This study aims to determine a predictor for the dislodgement of leads implanted in the RAS or RVS.

Methods

This retrospective cohort study enrolled 137 consecutive patients who underwent the cardiac implantable electronic devices implantation, using active fixation leads in the RAS and RVS. We compared the pacing threshold, R‐ or P‐wave amplitude, slew rate, and presence of the current of injury (COI) between dislodged and nondislodged leads.

Results

We performed lead fixation for 74 and 125 times in the RAS and RVS, respectively. Atrial lead dislodgement occurred five times (6.8%) intraoperatively and five times (6.8%) postoperatively, whereas ventricular lead dislodgement occurred eight times (6.4%) intraoperatively and three times (2.4%) postoperatively. Although there were no lead parameters that showed a significant difference common to RAS lead and RVS lead, the presence of the COI was significantly different between nondislodged and dislodged leads in both the RAS and RVS (atrial leads: 57.8% vs 0%, P < 0.001; ventricular leads: 67.5% vs 9.1%, P < 0.001). The positive predictive value of COI presence for predicting no lead dislodgement was 100% and 98.7% in the RAS and RVS, respectively.

Conclusion

Lead dislodgement is more likely when the COI is absent; documentation of COI should be pursued during lead implantation in challenging sites as the RAS and RVS.
Analysis of late reconnections after pulmonary vein isolation: Impact of interlesion contiguity and ablation index
Authors: Pedrote Alonso , Acosta Juan , Frutos‐López Manuel , Jáuregui‐Garrido Beatriz , Alarcón Francisco , Arana‐Rueda Eduardo
Published: March 2019

Background

Interlesion distance and ablation index (AI) have been proposed as parameters of radiofrequency (RF) lesion durability. This study analyzes the relationship between RF parameters of automatically acquired lesion tags and late reconnections in repeat pulmonary vein isolation (PVI) procedures.

Methods

One hundred fifty‐seven patients underwent contact force (CF)‐guided PVI with automatic acquisition of RF lesions. During follow‐up, 21 patients underwent a repeat PVI procedure. The relationship between RF parameters (power, CF, impedance drop, and AI) of the initial PVI procedure and reconnections observed at repeat PVI was analyzed. Visual gap was defined as the existence of a discontinuity between two RF lesions automatically acquired in the initial PVI procedure. Regional values of AI associated with lesion durability were identified.

Results

Twenty‐one patients were included. Three hundred thirty‐six segments and 2507 RF lesions were analyzed. The median interval between the initial and repeat PVI procedures was 17 (11‐24) months. All patients showed ≥1 reconnected segment. Sixty‐three segments (18.7%) were reconnected. Reconnected segments showed visual gaps more frequently than non‐reconnected segments (66.6% vs 17.6%; P < .001; negative predictive value 91.4%). The mean distance of visual gaps was 8 ± 2.8 mm. No differences were observed in power (31.4 ± 4.7 W vs 31 ± 4.1 W; P = .573), CF (14.4 ± 5.3 g vs 15.4 ± 5.4 g; P = .315), and impedance drop (6.9 ± 5.2 ohms vs 6.5 ± 3.8 ohms; P = .576) between reconnected and non‐reconnected segments. Among segments without visual gap, the minimum AI value was significantly higher in the non‐reconnected segments (325 ± 96.1 vs 204.7 ± 78.5; P < .001). No reconnections were observed in segments without visual gap and minimum AI ≥ 330/220 in anterior/posterior wall, respectively.

Conclusions

Contiguity between automatically acquired RF lesions and minimum AI value are the main determinants of long‐term PVI durability.
Multivariate Stochastic Volatility with Large and Moderate Shocks
Authors: Izzeldin Marwan , Tsionas Mike G. , Michaelides Panayotis G.
Published: March 2019

The paper proposes a multivariate stochastic volatility model where shifts in volatility are endogenously driven by large return shocks. The model proposed generalizes the univariate stochastic volatility model of Dendramis and colleagues to a multivariate context. Allowing for multivariate dependence permits the volatility of common return factors to affect individual stock returns volatility jointly. The model is further extended to allow for endogenous thresholds that depend on covariates. Model selection priors are introduced and the new techniques are applied by using data from the FTSE100-index.
HLA‐A, B, C, DRB1 and DQB1 allele and haplotype frequencies in volunteer bone marrow donors from Eastern Region of Saudi Arabia
Authors: Jawdat Dunia , Al‐Zahrani Mohsen , Al‐Askar Ahmed , Fakhoury Hana , Uyar Fatma Aytül , Hajeer Ali
Published: March 2019

We analyzed HLA allele and haplotype frequencies from donors from the Eastern region of Saudi Arabia. A cross‐sectional study was performed on 2405 bone marrow donors from the Eastern region. HLA typing was carried out by sequencing. The most common HLA allele groups were HLA‐A*02:01:01G (11.08%), A*01:01:01G (10.40%), HLA‐B*52:01:01G (8.79%), B*18:01:01G (8.07%), HLA‐C*04:01:01G (17.88%), C*12:03:01G (10.23%), HLA‐DRB1*10:01 (14.89%), DRB1*03:01:01G (14.10%), HLA‐DQB1*02:01:01G (24.53%) and DQB1*05:01:01G (20.17%). The most frequent HLA‐A~C~B~DRB1~DQB1 haplotypes were HLA‐A*01:03~C*15:05:01G~B*73:01~DRB1*10:01:01~DQB1*05:01:01G (3.11%) and HLA‐A*01:01:01G~C*12:02:01G~B*52:01:01G~DRB1*15:02:01~DQB1*06:01:01G (2.25%). When comparing the allele and haplotype frequencies of the Eastern regions' population to those from the Central region we found significant differences in several allele frequencies including A*01:01:01G (P ≤ 0.0001), B*52:01:01G (P ≤ 0.0001), B*18:01:01G (P = 0.0001), C*12:03:01G (P < 0.0001), DRB1*10:01:01 (P < 0.0001) and DQB1*05:01:01G (P < 0.0001). Our data confirms genetic heterogeneity among the Saudi population.
Autoimmune heparin‐induced thrombocytopenia and venous limb gangrene after aortic dissection repair: in vitro and in vivo effects of intravenous immunoglobulin
Authors: Arcinas Liane A. , Manji Rizwan A. , Hrymak Carmen , Dao Vi , Sheppard Jo‐Ann I. , Warkentin Theodore E.
Published: March 2019

BACKGROUND

Heparin‐induced thrombocytopenia (HIT) is a prothrombotic disorder characterized by heparin‐dependent antibodies that activate platelets (PLTs) via PLT FcγIIa receptors. “Autoimmune” HIT (aHIT) indicates a HIT subset where thrombocytopenia progresses or persists despite stopping heparin; aHIT sera activate PLTs strongly even in the absence of heparin (heparin‐independent PLT‐activating properties). Affected patients are at risk of severe complications, including dual macro‐ and microvascular thrombosis leading to venous limb gangrene. High‐dose intravenous immunoglobulin (IVIG) offers an approach to interrupt heparin‐independent PLT‐activating effects of aHIT antibodies.

CASE REPORT

A 78‐year‐old male who underwent cardiopulmonary bypass for aortic dissection developed aHIT, disseminated intravascular coagulation, and deep vein thrombosis; progression to venous limb gangrene occurred during partial thromboplastin time (PTT)‐adjusted bivalirudin infusion (underdosing from “PTT confounding”). Thrombocytopenia recovered with high‐dose IVIG, although the PLT count increase began only after the third dose of a 5‐day IVIG regimen (0.4 g/kg/day × 5 days). We reviewed case reports and case series of IVIG for treating HIT, focusing on various IVIG dosing regimens used.

RESULTS

Patient serum–induced PLT activation was inhibited in vitro by IVIG in a dose‐dependent fashion; inhibition of PLT activation by IVIG was much more marked in the absence of heparin versus the presence of heparin (0.2 U/mL). Our literature review indicated 1 g/kg × 2 IVIG dosing as most common for treating HIT, usually associated with rapid PLT count recovery.

CONCLUSION

Our clinical and laboratory observations support dose‐dependent efficacy of IVIG for decreasing PLT activation and thus correcting thrombocytopenia in aHIT. Our case experience and literature review suggests dosing of 1 g/kg IVIG × 2 for patients with severe aHIT.
Spontaneous appendico-renal fistula: clinical presentation and management of a previously unreported entity
Authors: Nayyar Rishi , Kumar Prashant
Published: March 2019

Entero-urinary fistulas are uncommon in urological practice and may have widely varying aetiologies ranging from benign to malignant or iatrogenic in nature. All permutations of entero-urinary fistulas have been reported in the literature except an appendico-renal fistula. Here, we present one such case, presenting with urinary tract infections and perineal urethrocutaneous fistulae. He was ultimately diagnosed to have a spontaneous appendico-renal fistula as underlying pathology behind the symptoms.
Evaluation of the NCCN guidelines using the RIGHT Statement and AGREE-II instrument: a cross-sectional review
Authors: Wayant Cole , Cooper Craig , Turner D’Arcy , Vassar Matt
Published: March 2019

Introduction

Robust, clearly reported clinical practice guidelines (CPGs) are essential for evidence-based clinical practice. The Reporting Items for practice Guidelines in HealThcare (RIGHT) Statement and Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument were published to improve the methodological and reporting quality in healthcare CPGs.

Methods

We applied the RIGHT Statement checklist and AGREE-II instrument to 48 National Comprehensive Cancer Network (NCCN) guidelines. Our primary objective was to assess the adherence to RIGHT and AGREE-II items. Since neither RIGHT nor AGREE-II can judge the clinical usefulness of a guideline, our study is designed to only focus on the methodological and reporting quality of each guideline.

Results

The NCCN guidelines demonstrated notable strengths and weaknesses. For example, RIGHT Statement items 19 (conflicts of interest), 7b (description of subgroups) and 13a (clear, precise recommendations) were fully reported in all guidelines. However, the guidelines inconsistently incorporated patient values and preferences and cost. Regarding the AGREE-II instrument, the NCCN guidelines scored highly on the domains 4 (clear, precise recommendations) and 6 (handling of conflicts of interest), but lowest on domain 2 (inclusion of all relevant stakeholders).

Conclusions

In this investigation, we found that NCCN CPGs demonstrate key strengths and weaknesses with respect to the reporting of key items essential to CPGs. We recommend the continued use of NCCN guidelines and improvements to weaknesses in reporting and methods. Doing so serves to improve the evidence delivered to healthcare providers, thus potentially improving patient care.
Pancreatic cancer ‘mismatch’ in Lynch syndrome
Authors: Hendifar Andrew E , Larson Brent K , Rojansky Rebecca , Guan Michelle , Gong Jun , Placencio Veronica , Tuli Richard , Hitchins Megan
Published: March 2019

Objective

Immune therapy with the PD1 inhibitor pembrolizumab has been approved to treat unresectable/metastatic solid tumours exhibiting mismatch repair (MMR) deficiency. Lynch syndrome (LS), caused by autosomal dominant germline mutations of a MMR gene, predisposes to the development of MMR-deficient cancers. We report a case ofMSH2-LS with an MMR-intact pancreatic ductal adenocarcinoma (PDAC) ineligible for treatment with pembrolizumab.

Design

Immunohistochemistry of MMR proteins was performed in each malignancy developed in aMSH2-LS patient to determine MMR status.

Results

The patient carried a pathogenicMSH2germline mutation and had a history of LS-type cancers, including endometrial carcinoma, colorectal adenocarcinoma, urothelial carcinoma of the bladder and PDAC. Three malignancies (endometrial, colorectal, urothelial) lacked MSH2 and MSH6 expression, consistent withMSH2-associated tumorigenesis. However, MSH2 and MSH6 expression were intact in the PDAC, suggesting the sporadic occurrence of the pancreatic tumour unrelated to the germlineMSH2mutation. These inconsistent MMR statuses among the tumours rendered the patient ineligible for the immunotherapy pembrolizumab.

Conclusion

Testing for MMR protein expression is recommended for each tumour in patients with LS, especially pancreatic, as discordant results may have profound effects on treatment opportunities. To our knowledge, this is the first documented case of MMR-intact PDAC in a patient withMSH2-LS.