bluuebunny/crossref_metadata_2025 huggingface dataset:
Stress testing journals: a quasi-experimental study of rejection rates of a previously published paper
Authors: Cobey Kelly D. , Rice Danielle B. , Lalu Manoj M. , Abramowitz Daniel , Ahmadzai Nadera , Cunningham Heather , Ayala Ana Patricia , Raffoul Hana , Khan Faizan , Shamseer Larissa , Moher David
Published: April 2020

Background

When a journal receives a duplicate publication, the ability to identify the submitted work as previously published, and reject it, is an assay to publication ethics best practices. The aim of this study was to evaluate how three different types of journals, namely open access (OA) journals, subscription-based journals, and presumed predatory journals, responded to receiving a previously published manuscript for review.

Methods

We performed a quasi-experimental study in which we submitted a previously published article to a random sample of 602 biomedical journals, roughly 200 journals from each journal type sampled: OA journals, subscription-based journals, and presumed predatory journals. Three hundred and three journals received a Word version in manuscript format, while 299 journals received the formatted publisher’s PDF version of the published article. We then recorded responses to the submission received after approximately 1 month. Responses were reviewed, extracted, and coded in duplicate. Our primary outcome was the rate of rejection of the two types of submitted articles (PDF vs Word) within our three journal types.

Results

We received correspondence back from 308 (51.1%) journals within our study timeline (32 days); (N = 46 predatory journals, N = 127 OA journals, N = 135 subscription-based journals). Of the journals that responded, 153 received the Word version of the paper, while 155 received the PDF version. Four journals (1.3%) accepted our paper, 291 (94.5%) journals rejected the paper, and 13 (4.2%) requested a revision. A chi-square test looking at journal type, and submission type, was significant (χ2 (4) = 23.50, p < 0.001). All four responses to accept our article came from presumed predatory journals, 3 of which received the Word format and 1 that received the PDF format. Less than half of journals that rejected our submissions did so because they identified ethical issues such as plagiarism with the manuscript (133 (45.7%)).

Conclusion

Few journals accepted our submitted paper. However, our findings suggest that all three types of journals may not have adequate safeguards in place to recognize and act on plagiarism or duplicate submissions.
Synthesis of the character impact compound raspberry ketone and additional flavoring phenylbutanoids of biotechnological interest with Corynebacterium glutamicum
Authors: Milke Lars , Mutz Mario , Marienhagen Jan
Published: April 2020

Background

The phenylbutanoid 4-(4-hydroxyphenyl)butan-2-one, commonly known as raspberry ketone, is responsible for the typical scent and flavor of ripe raspberries. Chemical production of nature-identical raspberry ketone is well established as this compound is frequently used to flavor food, beverages and perfumes. However, high demand for natural raspberry ketone, but low natural abundance in raspberries, render raspberry ketone one of the most expensive natural flavoring components.

Results

In this study, Corynebacterium glutamicum was engineered for the microbial synthesis of the character impact compound raspberry ketone from supplemented p-coumaric acid. In this context, the NADPH-dependent curcumin/dihydrocurcumin reductase CurA from Escherichia coli was employed to catalyze the final step of raspberry ketone synthesis as it provides a hitherto unknown benzalacetone reductase activity. In combination with a 4-coumarate: CoA ligase from parsley (Petroselinum crispum) and a monofunctional benzalacetone synthase from Chinese rhubarb (Rheum palmatum), CurA constitutes the synthetic pathway for raspberry ketone synthesis in C. glutamicum. The resulting strain accumulated up to 99.8 mg/L (0.61 mM) raspberry ketone. In addition, supplementation of other phenylpropanoids allowed for the synthesis of two other naturally-occurring and flavoring phenylbutanoids, zingerone (70 mg/L, 0.36 mM) and benzylacetone (10.5 mg/L, 0.07 mM).

Conclusion

The aromatic product portfolio of C. glutamicum was extended towards the synthesis of the flavoring phenylbutanoids raspberry ketone, zingerone and benzylacetone. Key to success was the identification of CurA from E. coli having a benzalacetone reductase activity. We believe, that the constructed C. glutamicum strain represents a versatile platform for the production of natural flavoring phenylbutanoids at larger scale.
Lattice complex assembled by noncompetitive anti-EGFR antibodies regulates actin cytoskeletal reorganization
Authors: Huang Dianshuai , Lu Tianqi , Du Xingyu , Xi Xi , Zhang Xin , Zhang Xitian , Zhang Haoran , Sun Fei
Published: April 2020

Background

Recent evidence of clinical trials highlights that the combination of two noncompetitive anti-EGFR antibodies can benefit patients with several cancers. Previous studies propose that a lattice complex assembled by antibodies and EGFR down-regulates surface EGFR by rapid internalization of the complex. However, there remains a paucity of evidence and understanding on the existence of a lattice complex on cell surface and its cellular processes of internalization.

Methods

Herein, we used three dimensions structured illumination microscopy to directly observe the actual morphology of the lattice complex formed on Hela cell membrane after noncompetitive anti-EGFR antibody combinations, and we explored the internalized mechanism of noncompetitive antibody combinations by constructing a PIP2 consumption system.

Result

We observed the lattice complex (length > 1 μm) on the surface of living cell after preincubation with Cetuximab and H11, but combination of Cetuximab and single domain antibody 7D12 fails to assemble the lattice, these results demonstrates the importance of symmetrical structure of conventional antibody for lattice formation. Interestingly, the lattice complex assembles along with cytoskeletal fibers, and its internalization recruits a large amount of PIP2 and triggers the rearrangement of F-actin.

Conclusions

The above data suggests that large-size lattice complex affects membrane fluidity and dynamic reorganization of cytoskeletal, which may be responsible for its rapid internalization. These new insight will aid in current rational combination design of anti-EGFR antibodies.
Enhanced inflammasome activation and reduced sphingosine-1 phosphate S1P signalling in a respiratory mucoobstructive disease model
Authors: Tran Hai B. , Macowan Matthew G. , Abdo Adrian , Donnelley Martin , Parsons David , Hodge Sandra
Published: April 2020

Background

Inflammasomes and sphingosine-1-phosphate (S1P) signalling are increasingly subject to intensive research in human diseases. We hypothesize that in respiratory muco-obstructive diseases, mucus obstruction enhances NLRP3 inflammasome activation and dysregulated S1P signalling.

Methods

Lung tissues from mice overexpressing the beta-unit of the epithelial sodium channel (βENaC) and their littermate controls were examined by histology, immunofluorescence and confocal microscopy, followed by ImageJ quantitative analysis.

Results

Lower airways in βENaC mice showed patchy patterns of mucus obstruction and neutrophil-dominant infiltrations. In contrast to a ubiquitous distribution of TNFα specks, significantly (p < 0.05) increased specks of bronchiolar NLRP3, IL-1β, and IgG in the βENaC mouse lungs were localized to the vicinity of mucus obstruction sites. Bright Spinster homologue 2 (SPNS2) at the epithelial apex and positive correlation with sphingosine kinase 1 (SPHK1) (R2 = 0.640; p < 0.001) supported the normal bronchial epithelium as an active generator of extracellular S1P. SPNS2 in βENaC mice was sharply reduced (38%, p < 0.05) and lost apical localization at sites of mucus obstruction. A significant (34%; p < 0.01) decrease in epithelial SPHK2 was also noted at mucus obstruction sites.

Conclusion

These results support that mucus obstruction may enhance NLRP3 inflammasome activation and dysregulated S1P signaling.
How many and which physicians? A comparative study of the evolution of the supply of physicians and specialist training in Brazil and Spain
Authors: Scheffer Mário César , Pastor-Valero Maria , Cassenote Alex Jones Flores , Compañ Rosique Antonio F.
Published: April 2020

Background

In the face of the medical workforce shortage, several countries have promoted the opening of medical schools and the expansion of undergraduate and specialization education in medicine. Few studies have compared the characteristics and effects of expanding the supply of general practitioners and specialist physicians between countries. Brazil and Spain, two countries with distinct historical processes and socioeconomic scenarios, yet both with universal public health systems and common aspects in training and medical work, have registered a significant increase in the number of physicians and can be used to understand the challenges of strategic planning for the medical workforce.

Methods

This study provides a descriptive approach using longitudinal data from official databases in Brazil and Spain from 1998 to 2017. Among the comparable indicators, the absolute numbers of physicians, the population size, and the physician’s ratio by inhabitants were used. The number of medical schools and undergraduate places in public and private institutions, the supply of residency training posts, and the number of medical specialists and medical residents per 100 000 inhabitants were also used to compare both countries. Seventeen medical specialties with the highest number of specialists and comparability between the two countries were selected for further comparison.

Results

Due to the opening of medical schools, the density of physicians per 1 000 inhabitants grew by 28% in Spain and 51% in Brazil between 1998 and 2017. In that period, Spain and Brazil increased the supply of annual undergraduate places by 60% and 137%, respectively. There is a predominance of private institutions providing available undergraduate places, and the supply of medical residency posts is smaller than the contingent of medical graduates/general practitioners each year.

Conclusion

Both countries have similar specialist densities in cardiology, dermatology, and neurosurgery specialties. However, family medicine and community in Spain has 91.27 specialists per 100 000 inhabitants, while in Brazil, the density is only 2.64. The comparative study indicated the complexity of the countries’ decisions on increasing the medical supply of general practitioners and specialist physicians. Research and planning policies on the medical workforce must be aligned with the actual health needs of populations and health systems.
Association between local immune cell infiltration, mismatch repair status and systemic inflammatory response in colorectal cancer
Authors: Gunnarsson Ulf , Strigård Karin , Edin Sofia , Gkekas Ioannis , Mustonen Harri , Kaprio Tuomas , Böckelman Camilla , Hagström Jaana , Palmqvist Richard , Haglund Caj
Published: April 2020

Background

Systemic inflammatory response in colorectal cancer (CRC) has been established as a prognostic factor for impaired cancer-specific survival, predominantly in patients with right-sided tumors. On the other hand, defective mismatch repair (dMMR) tumors, primarily located in the right colon, are known to have favorable survival and dense local immune infiltration. The aim of this study was to see if there is any form of relationship between these seemingly diverse entities.

Methods

Complete clinical and long-term survival data were retrieved for 316 CRC patients operated at Helsinki University Hospital between the years 1998 and 2003. Tissue microarrays were prepared from surgical specimens and further processed and analyzed for local immune cell infiltration using multispectral imaging with a Vectra quantitative pathology imaging system and Inform software. Multiplex immunohistochemistry was applied using antibodies against CD66b, CD8, CD20, FoxP3, CD68 and pan-Cytokeratin. After exclusions, data on immune infiltration were available for 275 patients. Mismatch repair status was determined by immunohistochemistry.

Results

CRP was seen to be an independent predictor of cancer-specific survival but not overall survival in uni- and multivariable (HR 1.01 (1.00–1.02); p = 0.028) analyses of non-irradiated patients. There was no significant difference in CRP according to mismatch repair status, but all cases (n = 10) with CRP ≥ 75 mg/l had proficient mismatch repair (pMMR). There was a significant negative correlation between intratumor stromal infiltration by T-regulatory FOXP3+ cells and CRP (p = 0.006). There was significantly lower intratumor stromal infiltration by FOXP3+ cells (p = 0.043) in the right colon compared to the rectum, but no significant difference in CRP (p = 0.44). CRP was not a predictor of overall survival (HR 0.99, 95% CI 0.98–1.01) nor cancer-specific survival in irradiated patients (HR 0.94, 95% CI 0.94–1.02).

Conclusions

There was a significant negative relationship between SIR, defined as an elevated CRP, and intratumor stromal infiltration by T-regulatory FOXP3+ cells. This and the fact that all cases with a CRP > 75 mg/l had pMMR suggests that SIR and dMMR are independent entities in CRC. Indeed, the general lack of difference in CRP between cases with dMMR and pMMR may be evidence of overlap in cases with a less pronounced SIR.
Study protocol: a cluster randomized trial to evaluate the effectiveness and implementation of onsite GeneXpert testing at community health centers in Uganda (XPEL-TB)
Authors: Reza Tania F. , Nalugwa Talemwa , Farr Katherine , Nantale Mariam , Oyuku Denis , Nakaweesa Annet , Musinguzi Johnson , Vangala Moksha , Shete Priya B. , Tucker Austin , Ferguson Olivia , Fielding Katherine , Sohn Hojoon , Dowdy David , Moore David A. J. , Davis J. Lucian , Ackerman Sara L. , Handley Margaret A. , Katamba Achilles , Cattamanchi Adithya
Published: April 2020

Background

Delays in diagnosis and treatment of tuberculosis (TB) remain common in high-burden countries. To improve case detection, substantial investments have been made to scale-up Xpert MTB/RIF (Xpert), a cartridge-based nucleic acid amplification test that can detect TB within 2 hours, as a replacement for sputum smear microscopy. However, the optimal strategy for implementation of Xpert testing remains unclear.

Methods

The Xpert Performance Evaluation for Linkage to Tuberculosis Care (XPEL-TB) trial uses an ultra-pragmatic, hybrid type II effectiveness-implementation design to assess the effectiveness and implementation of a streamlined strategy for delivery of Xpert testing in real-world settings. Twenty health centers with TB microscopy units were selected to participate in the trial, with ten health centers randomized to the intervention strategy (onsite molecular testing using GeneXpert Edge, process redesign to facilitate same-day TB diagnosis and treatment, and performance feedback) or routine care (onsite sputum smear microscopy plus referral of sputum samples to Xpert testing sites). The primary outcome is the number of patients with microbiologically confirmed TB who were initiated on treatment within 14 days of presentation to the health center, which reflects successful completion of the TB diagnostic evaluation process. Secondary outcomes include health outcomes (6-month vital status), as well as measures of the reach, adoption, and implementation of the intervention strategy.

Discussion

The design elements and implementation approach for the XPEL-TB trial were intentionally selected to minimize disruptions to routine care procedures, with the goal of limiting their influence on key primary and secondary outcomes. Trial findings may result in increased support and funding for rapid, onsite molecular testing as the standard-of-care for all patients being evaluated for TB.

Trial registration

US National Institutes of Health’s ClinicalTrials.gov, NCT03044158. Registered 06 February 2017.

Pan African Clinical Trials Registry, PACTR201610001763265. Registered 03 September 2016.
Participation of the ATR/CHK1 pathway in replicative stress targeted therapy of high-grade ovarian cancer
Authors: Gralewska Patrycja , Gajek Arkadiusz , Marczak Agnieszka , Rogalska Aneta
Published: April 2020

Ovarian cancer is one of the most lethal gynecologic malignancies reported throughout the world. The initial, standard-of-care, adjuvant chemotherapy in epithelial ovarian cancer is usually a platinum drug, such as cisplatin or carboplatin, combined with a taxane. However, despite surgical removal of the tumor and initial high response rates to first-line chemotherapy, around 80% of women will develop cancer recurrence. Effective strategies, including chemotherapy and new research models, are necessary to improve the prognosis. The replication stress response (RSR) is characteristic of the development of tumors, including ovarian cancer. Hence, RSR pathway and DNA repair proteins have emerged as a new area for anticancer drug development. Although clinical trials have shown poly (ADP-ribose) polymerase inhibitors (PARPi) response rates of around 40% in women who carry a mutation in the BRCA1/2 genes, PARPi is responsible for tumor suppression, but not for complete tumor regression. Recent reports suggest that cells with impaired homologous recombination (HR) activities due to mutations in TP53 gene or specific DNA repair proteins are specifically sensitive to ataxia telangiectasia and Rad3-related protein (ATR) inhibitors. Replication stress activates DNA repair checkpoint proteins (ATR, CHK1), which prevent further DNA damage. This review describes the use of DNA repair checkpoint inhibitors as single agents and strategies combining these inhibitors with DNA-damaging compounds for ovarian cancer therapy, as well as the new platforms used for optimizing ovarian cancer therapy.
Rare homozygous mutation in TUBB8 associated with oocyte maturation defect-2 in a consanguineous mating family
Authors: Xing Qiong , Wang Ruyi , Chen Beili , Li Lin , Pan Hong , Li Tengyan , Ma Xu , Cao Yunxia , Wang Binbin
Published: April 2020

Purpose

Variations in many genes may lead to the occurrence of oocyte maturation defects. To investigate the genetic basis of oocyte maturation defects, we performed clinical and genetic analysis of a pedigree.

Methods

The proband with oocyte maturation defect-2 receiving ovulation induction therapy and her parents were selected for clinical detection, whole exome sequencing and Sanger sequencing. One unrelated healthy woman received ovulation induction therapy as control. Mutations were assessed after frequency screening of public exome databases. Then homozygous variants shared by the proband and her parents were selected.

Results

Arrest of oocytes maturation was observed. A new missense mutation in TUBB8 (TUBB8: NM_177,987: exon 2: c. C161T: p. A54V) was identified, which was shown to be rare compared with public databases. The variant was highly conserved among primates, and was suggested to be deleterious by online software prediction.

Conclusions

The homozygote of this variant (TUBB8: NM_ 177,987: exon 2:c.C161T: p.A54V) might affect spindle assembly, cause arrest of oocyte maturation and lead to oocyte maturation defect-2.
Biological control of Aedes mosquito larvae with carnivorous aquatic plant, Utricularia macrorhiza
Authors: Couret Jannelle , Notarangelo Marco , Veera Sarashwathy , LeClaire-Conway Noah , Ginsberg Howard S. , LeBrun Roger L.
Published: April 2020

Background

Biological controls with predators of larval mosquito vectors have historically focused almost exclusively on insectivorous animals, with few studies examining predatory plants as potential larvacidal agents. In this study, we experimentally evaluate a generalist plant predator of North America, Utricularia macrorhiza, the common bladderwort, and evaluate its larvacidal efficiency for the mosquito vectors Aedes aegypti and Aedes albopictus in no-choice, laboratory experiments. We sought to determine first, whether U. macrorhiza is a competent predator of container-breeding mosquitoes, and secondly, its predation efficiency for early and late instar larvae of each mosquito species.

Methods

Newly hatched, first-instar Ae. albopictus and Ae. aegypti larvae were separately exposed in cohorts of 10 to field-collected U. macrorhiza cuttings. Data on development time and larval survival were collected on a daily basis to ascertain the effectiveness of U. macrorhiza as a larval predator. Survival models were used to assess differences in larval survival between cohorts that were exposed to U. macrorhiza and those that were not. A permutation analysis was used to investigate whether storing U. macrorhiza in laboratory conditions for extended periods of time (1 month vs 6 months) affected its predation efficiency.

Results

Our results indicated a 100% and 95% reduction of survival of Ae. aegypti and Ae. albopictus larvae, respectively, in the presence of U. macrorhiza relative to controls within five days, with peak larvacidal efficiency in plant cuttings from ponds collected in August. Utricularia macrorhiza cuttings, which were prey-deprived, and maintained in laboratory conditions for 6 months were more effective larval predators than cuttings, which were maintained prey-free for 1 month.

Conclusions

Due to the combination of high predation efficiency and the unique biological feature of facultative predation, we suggest that U. macrorhiza warrants further development as a method for larval mosquito control.
A unique thymus-derived regulatory T cell subset associated with systemic lupus erythematosus
Authors: Hanaoka Hironari , Nishimoto Tetsuya , Okazaki Yuka , Takeuchi Tsutomu , Kuwana Masataka
Published: April 2020

Background

Foxp3 is a marker for regulatory T cells (Treg cells), but recent studies have shown the plasticity and heterogeneity of CD4+Foxp3+ T cells. This study aimed to examine the phenotype and function of circulating CD4+Foxp3+ T cells in patients with systemic lupus erythematosus (SLE).

Methods

We enrolled 47 patients with SLE, 31 with organ-specific autoimmune diseases (15 with multiple sclerosis and 16 with primary immune thrombocytopenia), and 19 healthy subjects. Peripheral blood mononuclear cells were used to evaluate the proportion and phenotype of CD4+Foxp3+ cells using multicolor flow cytometry, the status of the Treg-specific demethylated region (TSDR) of the foxp3 gene by methylation-specific polymerase chain reaction, and the immunoregulatory function of CD4+CD25+ cells by allogeneic mixed lymphocyte reaction. Immunohistochemistry of renal biopsy specimens obtained from 6 patients with lupus nephritis and 5 with IgA nephropathy was conducted to detect IL-17A-expressing CD4+Foxp3+ cells.

Results

CD4+Foxp3+ T cells were increased in SLE patients compared with organ-specific autoimmune disease controls or healthy controls. Circulating CD4+Foxp3+ T cells were correlated with the disease activity of SLE. The increased CD4+Foxp3+ T cells in active SLE patients were mainly derived from thymus-derived Treg (tTreg) cells, as determined by a demethylated TSDR status, and represented a unique phenotype, upregulated expression of CD49d, CD161, and IL-17A, with immunosuppressive ability comparable to that of healthy controls. Finally, CD4+Foxp3+IL-17A+ cells were infiltrated into the renal biopsy specimens of patients with active lupus nephritis.

Conclusions

A unique tTreg subset with dichotomic immunoregulatory and T helper 17 phenotypes is increased in the circulation of SLE patients and may be involved in the pathogenic process of SLE.
The effectiveness of a longitudinal ultrasound curriculum for general pediatricians working in a Puerto Rican emergency department: a pilot study
Authors: Sepulveda-Ortiz Veronica , Warkentine Fred , Starr-Seal Rebecca , Rominger Anna
Published: April 2020

Background

The Hospital Pediatrico Universitario (HOPU) is the principal institution in Puerto Rico offering medical services to the children of the island and the Caribbean. There is limited use of point-of-care ultrasound (PoCUS) in their emergency department (ED) and obtaining an ultrasound through radiology is prohibitively time consuming. The objective of this study is to increase PoCUS knowledge and comfort by the ED physicians in the HOPU pediatric emergency department.

Results

Thirteen general pediatricians completed the entire PoCUS course, but only 10 completed both the pre- and post-tests and therefore included in the analysis (N = 10). Pretest scores ranged from 30 to 63.3% with a mean of 41.6% [standard deviation (SD) 9.95]. The posttest scores ranged from 55 to 96%, with a mean of 66.1% (SD 12.26). The mean difference in scores was 24.42% (95% confidence interval 17.9, 30.9) with a significance of p < 0.05 and range of 8.3–36.6%. Physician experience and confidence with each topic improved from baseline. After the course, the majority of the participants (> 70%) had at least some confidence in 5 of the 6 topics.

Conclusions

In EDs with limited resources, a longitudinal PoCUS educational curriculum is effective in improving the knowledge and comfort of physicians with limited PoCUS experience. The effectiveness of scheduled, repeated courses to refresh and refocus participants was highlighted following the unexpected challenges encountered during the course, including multiple natural disasters.
Inequalities of Green’s functions and positive solutions to nonlocal boundary value problems
Authors: Fan Shijie , Wen Pengxu , Zhang Guowei
Published: April 2020

In this paper, we discuss the positive solutions of beam equations with the nonlinearities including the slope and bending moment under nonlocal boundary conditions involving Stieltjes integrals. We pose some inequality conditions on nonlinearities and the spectral radius conditions on associated linear operators. These conditions mean that the nonlinearities have superlinear or sublinear growth. The existence of positive solutions is obtained by fixed point index on cones in $C^{2}[0,1]$C2[0,1], and some examples are given for beam equations subject to mixed integral and multi-point boundary conditions with sign-changing coefficients.
Comparative effect of dipeptidyl-peptidase 4 inhibitors on laboratory parameters in patients with diabetes mellitus
Authors: Nishida Yayoi , Takahashi Yasuo , Tezuka Kotoe , Akimoto Hayato , Nakayama Tomohiro , Asai Satoshi
Published: April 2020

Background

The purpose of this study was to evaluate and compare the effects on laboratory parameters among monotherapy with five DPP-4 inhibitors in patients with type 2 diabetes mellitus (DM).

Methods

We identified cohorts of new sitagliptin users (n = 879), vildagliptin users (n = 253), teneligliptin users (n = 260), alogliptin users (n = 237), and linagliptin users (n = 180) in patients with type 2 DM. We used a multivariate regression model to evaluate and compare the effects of the drugs on laboratory parameters including HbA1c concentration and serum concentrations of creatinine, estimated glomerular filtration rate, high density lipoprotein, total cholesterol, triglyceride, aspartate aminotransferase, and alanine aminotransferase among the five DPP-4 inhibitors up to 12 months.

Results

Our study showed a favorable effect on HbA1c concentration and a slightly unfavorable effect on serum creatinine concentration in users of the five DPP-4 inhibitors, a favorable effect on lipid metabolism in sitagliptin, vildagliptin, and alogliptin users, and a favorable effect on hepatic parameters in sitagliptin, alogliptin, and linagliptin users, in comparison of the baseline and exposure periods. However, there was no significant difference in mean change in the concentration of any laboratory parameter among the five groups of DPP-4 inhibitor users.

Conclusions

In this study, we showed the effect of five DPP-4 inhibitors on glycemic, renal, and lipid metabolism, and hepatic parameters. DPP-4 inhibitors are well-tolerated hypoglycemic drugs.
Knowledge and attitudes towards antibiotic use and resistance among undergraduate healthcare students at University of Rwanda
Authors: Nisabwe Lyduine , Brice Hirwa , Umuhire Marie Christine , Gwira Olivia , Harelimana Jean De Dieu , Nzeyimana Zephanie , Sebatunzi Osee Rurambya , Rusingiza Emmanuel Kamanzi , Hahirwa Innocent , Muvunyi Claude Mambo
Published: April 2020

Background

Antimicrobial resistance (AMR) is an imminent threat to modern medicine. As the efficacy of treatment regimens is reduced, mortality and morbidity attributed to infectious diseases is expected to rise dramatically across the globe. Antimicrobial stewardship and good prescription practices are critical to conserving available therapeutics; it is appropriate, therefore, to appraise our attitudes and knowledge of antimicrobial resistance, particularly for the future healthcare practitioners.

Methods

This is a descriptive cross-sectional study that was conducted among 282 medicals, dental and pharmacy students from the University of Rwanda. Questionnaires were used to collect data from the 4th to 29th March 2017.

Results

Students from Level 3 to level 6 have demonstrated a good knowledge on antibiotics and antimicrobial resistance. Generally, 95% (n = 218) agreed that the inappropriate use of antibiotics could lead to antibiotic resistance. It was found that 96% (n = 220) of the respondents had heard about AMR outside their degree courses. 49% (n = 112) of the participants reported that they are able to purchase antibiotics without a prescription. 96% (n = 220) agreed that it was important for healthcare students to be knowledgeable about antimicrobial resistance. Perhaps most surprisingly, it was found that 83% (n = 191) of participants were unfamiliar with the concept of antimicrobial stewardship and 49% (n = 21) had not yet discussed antimicrobial resistance as part of their education, albeit only 1% (n = 3) was completely unfamiliar with the term. Furthermore, 38% (n = 86) did not support that the antibiotics were overused in Rwanda, 23% (n = 10) did not agree that inappropriate antimicrobial use contributed to antimicrobial resistance, and 50% (n = 22) of participants agreed that antibiotics were indicated in the treatment of pain and inflammation.

Conclusions

The present study reports a moderate knowledge on AMR among the healthcare students. The gaps in the current formal training of healthcare individuals have been identified as well. We highlight the necessity to enhance educational approaches to introduce the key concepts of AMR and antimicrobial stewardship to the curriculum of healthcare students.
Factors influencing participation of underrepresented students in STEM fields: matched mentors and mindsets
Authors: Kricorian Katherine , Seu Michelle , Lopez Daniel , Ureta Elsie , Equils Ozlem
Published: April 2020

Background

Women and ethnic minorities remain underrepresented in science, technology, engineering, and math (STEM) fields. The goal of this pilot study is to better understand the beliefs and experiences of underrepresented US students pursuing STEM. Our focus was to gain insights into their mentorship experiences and preferences regarding having mentors who are gender and ethnicity matched. Environmental and psychological factors associated with participants’ decision to pursue STEM, such as family influences, academic mindsets, and attitudes towards STEM, were also studied.

Methods

We developed a survey tool based on published literature and established instruments, including measures of STEM belonging, science identity, and growth mindset, as well as measures assessing students’ views on their STEM participation. We surveyed members of a STEM-focused non-profit who were in college, graduate school, or were recent graduates.

Results

Forty-eight adults currently pursuing STEM responded to the survey. The majority (71%) were female and nearly all (96%) identified as an ethnic minority. Most reported knowing someone of their same gender (68%) or ethnicity (66%) with a STEM career who served as a role model. The majority (54%) stated that meeting a STEM professional of their own gender and ethnicity would be effective encouragement to pursue STEM. A similar percentage (56%) believed that media exposure to gender- and ethnicity-matched STEM professionals would be effective encouragement. Most (73%) demonstrated a growth mindset and had strong family support to pursue STEM (68%). Only two-thirds (66%) felt they belonged in STEM careers, and 30% agreed that people in their STEM classes are a lot like them.

Conclusion

This study contributes additional information on the views and experiences of diverse students actively pursuing STEM. Most participants indicated the importance of meeting and being mentored in STEM by those of their same gender and ethnicity, either in person or through media. Future educational efforts to increase STEM diversity should consider students’ mentorship preferences and facilitate interactions with matched-background mentors accordingly, with consideration given to the use of media. Educators should focus on inclusive learning by highlighting the accomplishments of diverse STEM professionals, to help strengthen feelings of STEM belonging.
Multiple cholangiocarcinomas in the intrahepatic and extrahepatic biliary tree due to dichloromethane exposure: a case report
Authors: Ogawa Daisuke , Hayashi Hiromitsu , Kitamura Fumimasa , Uemura Norio , Miyata Tatsunori , Okabe Hirohisa , Imai Katsunori , Yamasita Yoichi , Kubo Shoji , Baba Hideo
Published: April 2020

Background

An outbreak of cholangiocarcinoma in Japan has led to widespread concern among workers in printing plants. In March 2013, the Japanese Ministry of Health, Labour and Welfare, confirmed a causal relationship between cholangiocarcinoma and long-term exposure to dichloromethane (DCM) and 1,2-dichloropropane (DCP), which were widely used in printing plants. We herein report a rare case of successful radical resection of multiple cholangiocarcinomas in the intrahepatic and extrahepatic bile ducts caused by past exposure to DCM.

Case presentation

A 54-year-old man developed brown urine 22 years after his last exposure to DCP and DCM. He had an 11-year history of working at a printing plant from the age of 21 to 31 years and dealt with organic solvents during his employment. Enhanced computed tomography revealed a thickened distal bile duct wall with upstream biliary dilatation and multiple intrahepatic cholangiocarcinomas located in liver segments III, VI, and VIII. Biopsy of the distal bile duct wall revealed adenocarcinoma, and a diagnosis of distal cholangiocarcinoma was made. Tumor marker levels were within the reference range (carcinoembryonic antigen, 3.3 ng/mL; carbohydrate antigen 19-9, 25.4 U/mL; SPAN-1, 13 U/mL; and DUPAN-2, 33 U/mL). The multiple intrahepatic and extrahepatic bile duct cancers were treated by subtotal stomach-preserving pancreatoduodenectomy and partial hepatectomy of segments III, VI, and VIII. Pathological examination of the surgical specimens revealed multiple cholangiocarcinomas with well-differentiated adenocarcinoma in the biliary tree. The patient was still alive without recurrence 17 months after the operation.

Conclusions

We experienced a rare case of multiple cholangiocarcinomas in the intrahepatic and extrahepatic bile ducts that developed 22 years after the patient’s last exposure to DCP and DCM. Long-term and careful follow-up is required for workers with an occupational history of exposure to organic solvents because of the risk of development of cholangiocarcinoma.
Prognostic factors of delayed cerebral ischemia after subarachnoid hemorrhage including CT perfusion: a prospective cohort study
Authors: Abdel-Tawab Mohamed , Hasan Afaf A. , Ahmed Mohamed A. , Seif Hany M. A. , Yousif Hazem A.
Published: April 2020

Background

Delayed cerebral ischemia (DCI) is the worst sequel following subarachnoid hemorrhage (SAH), representing a challenge in prediction and prevention. The current study aims to identify the optimum predictors of DCI including CT perfusion (CTP) and to determine the best prognostic thresholds.

This prospective study included 49 SAH patients. All patients were treated with the standard therapy and underwent non-contrast CT, CTP, and CTA within 3 days after SAH. Hunt and Hess and Fisher scales were assessed besides quantitative CTP parameters. The primary endpoint was DCI within 21 days after SAH, defined as clinical deterioration or infarction.

Results

Out of 49 eligible patients with SAH, 9 patients developed DCI. Univariate analysis revealed that Hunt and Hess scale, Fisher scale, the presence of a cerebral aneurysm, and mean transit time (MTT) were predictive for DCI. Diagnostic threshold values by ROC curve analysis with optimal sensitivity and specificity were Hunt and Hess scale > 2, Fisher scale > 2, and MTT of 4.65 s.

Conclusion

MTT is a sensitive and specific predictor of DCI. However, Hunt and Hess scale has the optimal sensitivity and specificity to distinguish between patients who developed DCI and clinically stable patients.
Beyond Tumor PD-L1: Emerging Genomic Biomarkers for Checkpoint Inhibitor Immunotherapy
Authors: Lagos Galina G. , Izar Benjamin , Rizvi Naiyer A.
Published: April 2020

Despite the success of immune checkpoint blockade as a strategy for activating an antitumor immune response and promoting cancer regression, only a subset of patients have durable clinical benefit. Efforts are ongoing to identify robust biomarkers that can effectively predict treatment response to immune checkpoint inhibitors (ICIs). Although PD-L1 expression is useful for stratifying patients, it is an imperfect tool. Comprehensive next-generation sequencing platforms that are readily used in clinical practice to identify a tumor’s potentially actionable genetic alterations also reveal tumor genomic features, including tumor mutation burden (TMB), that may impact the response to ICIs. High TMB enhances tumor immunogenicity through increased numbers of tumor neoantigens that may promote an immune response. Defective DNA repair, leading to microsatellite instability, is an endogenous mechanism for increased tumor TMB that augments response to anti–PD-1 blockade. Alternatively, DNA damage from exogenous factors is responsible for high TMB seen in melanoma, lung cancer, and urothelial carcinoma, among tumor subtypes with higher response rates to ICIs. In this review, we summarize data supporting the use of TMB as a biomarker as well as its known limitations. We also highlight specific tumor suppressor genes and oncogenes that are under investigation as biomarkers for ICI response and resistance. Efforts are ongoing to delineate which genomic tumor characteristics can eventually be utilized in clinical practice to ascertain the benefit of ICIs for an individual patient.
Maternal Glycemia During Pregnancy and Child Carotid Intima Media Thickness, Pulse Wave Velocity, and Augmentation Index
Authors: Yuan Wen Lun , Lin Jinjie , Kramer Michael S , Godfrey Keith M , Gluckman Peter D , Chong Yap-Seng , Shek Lynette P , Tan Kok Hian , Chan Shiao-Yng , Eriksson Johan G , Yap Fabian , Lee Yung Seng , Choo Jonathan T L , Ling Lieng Hsi
Published: April 2020

Background

In women without diabetes, little is known about the consequences of hyperglycemia during pregnancy for the offspring’s cardiovascular structure and function.

Objective

To investigate the association of maternal glycemia during pregnancy with cardiovascular risk markers in their children in GUSTO, a Singaporean birth cohort study.

Methods

Around 26 weeks’ gestation, a 75 g oral glucose tolerance test was performed and fasting plasma glucose (FPG) and 2-hour postprandial plasma glucose (PPPG) concentrations were measured. Gestational diabetes mellitus (GDM) was defined using WHO 1999 diagnostic criteria. At 6 years of age, we measured the child’s carotid intima-media thickness (cIMT), carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index (AIx), and blood pressure (BP). Association of maternal glycemia during pregnancy with cardiovascular risk markers in their children were analyzed using multiple linear and logistic regressions.

Results

Analysis were performed on 479 mother–child dyads. Higher maternal FPG was associated with higher cIMT and, in males, with a higher cfPWV in the offspring (adjusted β [CI 95%], cIMT: 0.08 per 10mm increase [0.02; 0.15], cfPWV: 0.36 m/s [0.01; 0.70]). Higher 2-hour PPPG was associated with higher cfPWV and AIx. Gestational diabetes mellitus was associated with higher AIx. No association was found between maternal glycemia and their offspring blood pressure.

Conclusions

among mothers without pre-existing diabetes, higher glycemia during pregnancy was associated with mild structural and functional vascular changes in their children at 6 years of age across a continuum. These results support the necessity to monitor maternal glycemia during pregnancy even in the absence of pre-existing diabetes or diagnosed GDM.
An Ultrasensitive Routine LC-MS/MS Method for Estradiol and Estrone in the Clinically Relevant Sub-Picomolar Range
Authors: Bertelsen Bjørn-Erik , Kellmann Ralf , Viste Kristin , Bjørnevik Anne Turid , Eikesdal Hans Petter , Lønning Per Eystein , Sagen Jørn V , Almås Bjørg
Published: April 2020

Background

Current analytical routine methods lack the sensitivity to monitor plasma estrogen levels in breast cancer patients treated with aromatase inhibitors. Such monitoring is warranted for premenopausal patients treated with an aromatase inhibitor and an LH-releasing hormone analogue in particular. Therefore, we aimed to develop a routine tandem mass spectroscopy combined with liquid chromatography (LC-MS/MS) method for estradiol (E2) and estrone (E1) for use in the sub-picomolar range.

Method

Calibrators, quality controls (QC), or serum samples were spiked with isotope-labeled internal standard and purified by liquid-liquid extraction. The reconstituted extracts were analyzed by LC-MS/MS in negative electrospray ionization mode. QCs at 6 levels made from pooled patient sera were used to validate the accuracy, sensitivity, and precision of the method.

Results

We achieved limits of quantification of 0.6 pmol/L (0.16 pg/mL) for E2 and 0.3 pmol/L (0.07 pg/mL) for E1. The coefficient of variation was below 9.0% at all QC levels for E2 (range, 1.7-153 pmol/L), and below 7.8% for E1 (range, 1.7-143 pmol/L). The method is traceable to the E2 reference standard BCR576. Reference ranges for E2 and E1 in healthy, postmenopausal women were obtained, for E2: 3.8 to 36 pmol/L, for E1: 22 to 122 pmol/L. We measured and confirmed ultra-low E2 and E1 concentrations in sera from patients on the aromatase inhibitors letrozole or exemestane.

Conclusion

This ultrasensitive LC-MS/MS method is suitable for routine assessment of serum E1 and E2 levels in breast cancer patients during estrogen suppression therapy. The method satisfies all requirements for measurement of E2 in the clinical setting as stated by the Endocrine Society in 2013.

Precis

We report an ultrasensitive LCMS/MS routine assay that measures pretreatment and suppressed levels of estradiol/estrone during aromatase inhibitor treatment of postmenopausal breast cancer patients.
WNT regulates programmed muscle remodeling through PLC-β and calcineurin in C. elegans males
Authors: LeBoeuf Brigitte , Chen Xin , Garcia Luis Rene
Published: April 2020

A muscle's ability to breakdown and reform fibers is vital for development; however if unregulated, abnormal muscle remodeling can occur, such as in the heart following cardiac infarction. To study how normal developmental remodeling is mediated, we used fluorescently tagged actin, mutant analyses, Ca2+ imaging, and controlled Ca2+ release to determine the mechanisms regulating a conspicuous muscle change that occurs in C. elegans males. In hermaphrodites and larval males, the single-cell anal depressor muscle, used for waste expulsion, contains bilateral dorsal-ventral sarcomeres. However prior to male adulthood, the muscle sex-specifically remodels its sarcomeres anterior-posteriorly to promote copulation behavior. Although WNT signaling and calcineurin have been implicated separately in muscle remodeling, unexpectedly we found that they participate in the same pathway. We show that WNT signaling through Go and PLC-β results in sustained Ca2+ release via IP(3) and ryanodine receptors to activate calcineurin. These results highlight the utility of this new model in identifying additional molecules involved in muscle remodeling.
Atypical basement membranes and basement membrane diversity – what is normal anyway?
Authors: Pastor-Pareja José C.
Published: April 2020

The evolution of basement membranes (BMs) played an essential role in the organization of animal cells into tissues and diversification of body plans. The archetypal BM is a compact extracellular matrix polymer containing laminin, nidogen, collagen IV and perlecan (LNCP matrix) tightly packed into a homogenously thin planar layer. Contrasting this clear-cut morphological and compositional definition, there are numerous examples of LNCP matrices with unusual characteristics that deviate from this planar organization. Furthermore, BM components are found in non-planar matrices that are difficult to categorize as BMs at all. In this Review, I discuss examples of atypical BM organization. First, I highlight atypical BM structures in human tissues before describing the functional dissection of a plethora of BMs and BM-related structures in their tissue contexts in the fruit fly Drosophila melanogaster. To conclude, I summarize our incipient understanding of the mechanisms that provide morphological, compositional and functional diversity to BMs. It is becoming increasingly clear that atypical BMs are quite prevalent, and that even typical planar BMs harbor a lot of diversity that we do not yet comprehend.
Body surface temperature responses to food restriction in wild and captive great tits
Authors: Winder Lucy A. , White Stewart A. , Nord Andreas , Helm Barbara , McCafferty Dominic J.
Published: April 2020

During winter at temperate and high latitudes, the low ambient temperatures, limited food supplies and short foraging periods mean small passerines show behavioural, morphological and physiological adaptations to reduce the risk of facing energy shortages. Peripheral tissues vasoconstrict in low ambient temperatures to reduce heat loss and cold injury. Peripheral vasoconstriction has been observed with food restriction in captivity but has yet to be explored in free-ranging animals. We experimentally food restricted both wild and captive great tits (Parus major) during winter months and measured surface temperatures of the bill and eye region using thermal imaging, to investigate whether birds show rapid local heterothermic responses, which may reduce their thermoregulatory costs when facing a perceived imminent food shortage. Our results of a continuously filmed wild population showed that bill temperature was immediately reduced in response to food restriction compared with when food was available ad libitum, an apparent autonomic response. Such immediacy implies a ‘pre-emptive’ response before the bird experiences any shortfalls in energy reserves. We also demonstrate temporal variation in vasoconstriction of the bill, with bill temperature gradually rising throughout the food restriction after the initial drop. Eye-region temperature in the wild birds remained at similar levels throughout food restriction compared with unrestricted birds, possibly reflecting the need to maintain steady circulation to the central nervous and visual systems. Our findings provide evidence that birds selectively allow the bill to cool when a predictable food supply is suddenly disrupted, probably as a means of minimising depletion of body reserves for a perceived future shortage in energy.