bluuebunny/crossref_metadata_2025 huggingface dataset:
A stepped wedge trial of efficacy and scalability of a virtual clinical pharmacy service (VCPS) in rural and remote NSW health facilities
Authors: Allan Julaine , Nott Shannon , Chambers Brett , Hawthorn Ged , Munro Alice , Doran Chris , Oldmeadow Chris , Coleman Clare , Saksena Teesta
Published: May 2020

Background

Medication errors are a leading cause of mortality and morbidity. Clinical pharmacy services provided in hospital can reduce medication errors and medication related harm. However, few rural or remote hospitals in Australia have a clinical pharmacy service. This study will evaluate a virtual clinical pharmacy service (VCPS) provided via telehealth to eight rural and remote hospitals in NSW, Australia.

Methods

A stepped wedge cluster randomised trial design will use routinely collected data from patients’ electronic medical records (n = 2080) to evaluate the VCPS at eight facilities. The sequence of steps is randomised, allowing for control of potential confounding temporal trends. Primary outcomes are number of medication reconciliations completed on admission and discharge. Secondary outcomes are length of stay, falls and 28 day readmissions. A cost-effectiveness analysis (CEA) and cost-benefit analysis (CBA) will be conducted. The CEA will answer the question of whether the VCPS is more cost-effective compared to treatment as usual; the CBA will consider the rate of return on investing in the VCPS. A patient experience measure (n = 500) and medication adherence questionnaire (n = 100 pre and post) will also be used to identify patient responses to the virtual service. Focus groups will investigate implementation from hospital staff perspectives at each site.

Analyses of routine data will comprise generalised linear mixed models. Descriptive statistical analysis will summarise patient experience responses. Differences in medication adherence will be compared using linear regression models. Thematic analysis of focus groups will identify barriers and facilitators to VCPS implementation.

Discussion

We aim to demonstrate the effectiveness of virtual pharmacy interventions for rural populations, and inform best practice for using virtual healthcare to improve access to pharmacy services. It is widely recognised that clinical pharmacists are best placed to reduce medication errors. However, pharmacy services are limited in rural and remote hospitals. This project will provide evidence about ways in which the benefits of hospital pharmacists can be maximised utilising telehealth technology. If successful, this project can provide a model for pharmacy delivery in rural and remote locations.

Trial registration

Australian New Zealand Clinical Trials Registry (ANZCTR) -ACTRN12619001757101 Prospectively registered on 11 December 2019. Record available from: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378878&isReview=true
The three numbers you need to know about healthcare: the 60-30-10 Challenge
Authors: Braithwaite Jeffrey , Glasziou Paul , Westbrook Johanna
Published: May 2020

Background

Healthcare represents a paradox. While change is everywhere, performance has flatlined: 60% of care on average is in line with evidence- or consensus-based guidelines, 30% is some form of waste or of low value, and 10% is harm. The 60-30-10 Challenge has persisted for three decades.

Main body

Current top-down or chain-logic strategies to address this problem, based essentially on linear models of change and relying on policies, hierarchies, and standardisation, have proven insufficient. Instead, we need to marry ideas drawn from complexity science and continuous improvement with proposals for creating a deep learning health system. This dynamic learning model has the potential to assemble relevant information including patients’ histories, and clinical, patient, laboratory, and cost data for improved decision-making in real time, or close to real time. If we get it right, the learning health system will contribute to care being more evidence-based and less wasteful and harmful. It will need a purpose-designed digital backbone and infrastructure, apply artificial intelligence to support diagnosis and treatment options, harness genomic and other new data types, and create informed discussions of options between patients, families, and clinicians. While there will be many variants of the model, learning health systems will need to spread, and be encouraged to do so, principally through diffusion of innovation models and local adaptations.

Conclusion

Deep learning systems can enable us to better exploit expanding health datasets including traditional and newer forms of big and smaller-scale data, e.g. genomics and cost information, and incorporate patient preferences into decision-making. As we envisage it, a deep learning system will support healthcare’s desire to continually improve, and make gains on the 60-30-10 dimensions. All modern health systems are awash with data, but it is only recently that we have been able to bring this together, operationalised, and turned into useful information by which to make more intelligent, timely decisions than in the past.
Why do graduates choose to work in a less attractive specialty? A cross-sectional study on the role of personal values and expectations
Authors: Nguyen Van Anh Thi , Könings Karen D. , Wright E. Pamela , Kim Giang Bao , Luu Hoat Ngoc , Scherpbier Albert J. J. A. , van Merriënboer Jeroen J. G.
Published: May 2020

Background

Primary health care (PHC), of which preventive medicine (PM) is a subspecialty, will have to cope with a deficiency of staff in the future, which makes the retention of graduates urgent. This study was conducted in Vietnam, where PM is an undergraduate degree in parallel to medical training. It aims to identify facilitating and hindering factors that impact recruitment and retention of PM graduates in the specialty.

Methods

A cross-sectional study enrolled 167 graduates who qualified as PM doctors from a Vietnamese medical school, between 2012 and 2018. Data were collected via an online questionnaire that asked participants about their motivation and continuation in PM, the major life roles that they were playing, and their satisfaction with their job. Multiple regression analyses were used to identify which life roles and motivational factors were related to the decision to take a PM position and to stay in the specialty, as well as how these factors held for subgroups of graduates (men, women, graduates who studied PM as their first or second study choice).

Results

Half of the PM graduates actually worked in PM, and only one fourth of them expressed the intention to stay in the field. Three years after qualification, many graduates had not yet decided whether to pursue a career in PM. Satisfaction with opportunities for continuous education was rated as highly motivating for graduates to choose and to stay in PM. Responsibility for taking care of parents motivated male graduates to choose PM, while good citizenship and serving the community was associated with the retention of graduates for whom PM was their first choice.

Conclusions

The findings demonstrate the importance of social context and personal factors in developing primary care workforce policy. Providing opportunities for continued education and enhancing the attractiveness of PM as an appropriate specialty to doctors who are more attached to family and the community could be solutions to maintaining the workforce in PM. The implications could be useful for other less popular specialties that also struggle with recruiting and retaining staff.
PDK1 regulates the survival of the developing cortical interneurons
Authors: Wei Yongjie , Han Xiaoning , Zhao Chunjie
Published: May 2020

Inhibitory interneurons are critical for maintaining the excitatory/inhibitory balance. During the development cortical interneurons originate from the ganglionic eminence and arrive at the dorsal cortex through two tangential migration routes. However, the mechanisms underlying the development of cortical interneurons remain unclear. 3-Phosphoinositide-dependent protein kinase-1 (PDK1) has been shown to be involved in a variety of biological processes, including cell proliferation and migration, and plays an important role in the neurogenesis of cortical excitatory neurons. However, the function of PDK1 in interneurons is still unclear. Here, we reported that the disruption of Pdk1 in the subpallium achieved by crossing the Dlx5/6-Cre-IRES-EGFP line with Pdk1fl/fl mice led to the severely increased apoptosis of immature interneurons, subsequently resulting in a remarkable reduction in cortical interneurons. However, the tangential migration, progenitor pools and cell proliferation were not affected by the disruption of Pdk1. We further found the activity of AKT-GSK3β signaling pathway was decreased after Pdk1 deletion, suggesting it might be involved in the regulation of the survival of cortical interneurons. These results provide new insights into the function of PDK1 in the development of the telencephalon.
Genetic alteration, RNA expression, and DNA methylation profiling of coronavirus disease 2019 (COVID-19) receptor ACE2 in malignancies: a pan-cancer analysis
Authors: Chai Peiwei , Yu Jie , Ge Shengfang , Jia Renbing , Fan Xianqun
Published: May 2020

The novel coronavirus (2019-nCoV) is an emerging causative agent that was first described in late December 2019 and causes a severe respiratory infection in humans. Notably, many of affected patients of COVID-19 were people with malignancies. Moreover, cancer has been identified as an individual risk factor for COVID-19. In addition, the expression of angiotensin converting enzyme 2 (ACE2), the receptor of COVID-19, were aberrantly expressed in many tumors. However, a systematic analysis of ACE2 aberration remained to be elucidated in human cancers. Here, we analyzed genetic alteration, RNA expression, and DNA methylation of ACE2 across over 30 tumors. Notably, overexpression of ACE2 have been observed in including colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). In addition, hypo DNA methylation of ACE2 has also been identified in most of these ACE2 highly expressed tumors. Conclusively, our study for the first time curated both genetic and epigenetic variations of ACE2 in human malignancies. Notably, because our study is a bioinformatics assay, further functional and clinical validation is warranted.
The HOME Study: Statistical and economic analysis plan for a randomised controlled trial comparing the addition of Proactive Psychological Medicine to usual care, with usual care alone, on the time spent in hospital by older acute hospital inpatients
Authors: Magill Nicholas , White Ian R. , Walker Jane , Burke Katy , Toynbee Mark , van Niekerk Maike , Yang Fan , Walker Simon , Sculpher Mark , Sharpe Michael , Frost Chris
Published: May 2020

Background

Prolonged acute hospital stays are a problem for older people and for health services. Failure to effectively manage the psychological and social aspects of illness is an important cause of prolonged hospital stay. Proactive Psychological Medicine (PPM) is a new way of providing psychiatry services to medical wards which is proactive, focussed, intensive and integrated with medical care. The primary aim of PPM is to reduce the time older people spend in hospital because of unmanaged psychological and social problems. The HOME Study will test the effectiveness and cost-effectiveness of PPM.

Methods/design

The study is a two-arm, parallel-group, randomised, controlled superiority trial with linked health economic analysis and an embedded process evaluation. The target population is people aged 65 years and older admitted to acute hospitals. Participants will be randomly allocated to either usual care plus PPM or usual care alone. The primary outcome is the number of days spent as an inpatient in a general hospital in the month following randomisation. Secondary outcomes include quality of life, cognitive function, independent functioning, symptoms of anxiety and depression, and experience of hospital stay. The cost-effectiveness of usual care plus PPM compared with usual care alone will be assessed using quality-adjusted life-years as an outcome as well as costs from the NHS perspective.

Discussion

This update to the published trial protocol gives a detailed plan of the statistical and economic analysis of The HOME Study.

Trial registration

ISRCTN registry,ISRCTN86120296. Registered on 3 January 2018.
IgG4-related aortitis/periaortitis and periarteritis: a distinct spectrum of IgG4-related disease
Authors: Peng Linyi , Zhang Panpan , Li Jieqiong , Liu Zheng , Lu Hui , Zhu Liang , Wang Xiaorong , Teng Fei , Li Xuemei , Guo Huifang , Fei Yunyun , Zhang Wen , Zhao Yan , Zeng Xiaofeng , Zhang Fengchun
Published: May 2020

Background

Large vessels could be involved in immunoglobulin (Ig)-G4-related disease (IgG4-RD). This study aimed to clarify the clinical features and evaluate the treatment efficacy for IgG4-RD with aortitis/periaortitis and periarteritis (PAO/PA).

Methods

This study prospectively enrolled 587 patients with IgG4-RD with a follow-up time of more than 6 months. The distribution of IgG4-related PAO/PA was classified into four types: type 1, thoracic aorta; type 2a, abdominal aorta; type 2b, abdominal aorta and iliac artery; type 2c, iliac artery; type 3, thoracic and abdominal aorta; and type 4, other arteries. Patient’s demographic data, clinical characteristics, laboratory parameters, and treatment efficacy were analyzed.

Results

Of 587 IgG4-RD patients, 89 (15.2%) had PAO/PA. The average age was 58.3 ± 11.1 years, with male predominance (85.4%). Vessels affected were as follows: abdominal aorta (83.1%), iliac artery (70.8%), thoracic aorta (13.5%), and other vessels (13.5%). The most prevalent distribution type of IgG4-related PAO/PA was type 2b, with 74 (83.1%) patients, followed by type 2a, type 2c, type 3, and type 1. Fifty-five (61.8%) PAO/PA patients had hydronephrosis, with renal insufficiency occurring in 43 (48.3%), and 31 (34.8%) PAO/PA patients had D-J stent drainage due to severe ureteral obstruction. After treatment with a glucocorticoid and immunosuppressants, 82% patients achieved remission with shrinking of the perivascular mass by more than 30%.

Conclusions

IgG4-RD with PAO/PA was distinct from non-PAO/PA in demographic features, organ involvement distribution, inflammatory markers, and serum IgG4 and IgE. The most common affected vessel was the abdominal aorta, and most patients responded well with treatment.
The use of cyclic dipeptide producing LAB with potent anti-aflatoxigenic capability to improve techno-functional properties of clean-label bread
Authors: Ebrahimi Maryam , Sadeghi Alireza , Mortazavi Seyed Ali
Published: May 2020

Purpose

The aim of the present study was to evaluate the antifungal activity, anti-aflatoxigenic capability, and technological functionality of the selected lactic acid bacteria (LAB) isolated from wheat sourdough.

Methods

The preselected LAB isolates were screened based on their antifungal activities and acidification capacities. Then, the antifungal compounds were identified using gas chromatography/mass spectrometry in the selected LAB culture filtrate obtained from its preparative thin-layer chromatography. The HPLC-based analysis was also used to investigate the anti-aflatoxigenic potentials of the selected LAB isolate. Finally, controlled sourdough (containing selected LAB isolate as starter culture) was used to produce loaf bread, and properties of the product were evaluated in terms of hardness, phytic acid content, overall acceptability, and surface moldiness.

Results

Molecular approaches led to the identification of Pediococcus pentosaceus as the selected LAB isolate. In vitro and in situ antifungal activities of the selected LAB against Aspergillus niger were verified. Antifungal metabolites of the LAB included fatty acid ester, hydroxylated fatty acid ester, an antimicrobial compound, and cyclic dipeptide. Potent anti-aflatoxigenic capabilities of the LAB isolate and cyclic dipeptide (which was identified in the antifungal fraction of the LAB) were also verified. To our best knowledge, the cyclic dipeptide detected in the present study has never been shown before to possess anti-aflatoxigenic effect. Furthermore, the results revealed that controlled sourdough improved the techno-functional properties of the produced loaf wheat bread.

Conclusion

Altogether, our findings indicate that the selected P. pentosaceus isolate exhibiting proper characteristics can be used as a bio-preservative and bio-improver in the processing of clean-label breads.
Prospects of Indole derivatives as methyl transfer inhibitors: antimicrobial resistance managers
Authors: Tha Suprim , Shakya Sapana , Malla Rajani , Aryal Pramod
Published: May 2020

Background

It is prudent that novel classes of antibiotics be urgently developed to manage the WHO prioritized multi-drug resistant (MDR) pathogens posing an unprecedented medical crisis. Simultaneously, multiple essential proteins have to be targeted to prevent easy resistance development.

Methods

An integration of structure-based virtual screening and ligand-based virtual screening was employed to explore the antimicrobial properties of indole derivatives from a compound database.

Results

Whole-genome sequences of the target pathogens were aligned exploiting DNA alignment potential of MAUVE to identify putative common lead target proteins. S-adenosyl methionine (SAM) biosynthesizing MetK was taken as the lead target and various literature searches revealed that SAM is a critical metabolite. Furthermore, SAM utilizing CobA involved in the B12 biosynthesis pathway, Dam in the regulation of replication and protein expression, and TrmD in methylation of tRNA were also taken as drug targets. The ligand library of 715 indole derivatives chosen based on kinase inhibition potential of indoles was created from which 102 were pursued based on ADME/T scores. Among these, 5 potential inhibitors of MetK in N. gonorrhoeae were further expanded to molecular docking studies in MetK proteins of all nine pathogens among which 3 derivatives exhibited inhibition potential. These 3 upon docking in other SAM utilizing enzymes, CobA, Dam, and TrmD gave 2 potential compounds with multiple targets. Further, docking with human MetK homolog also showed probable inhibitory effects however SAM requirements can be replenished from external sources since SAM transporters are present in humans.

Conclusions

We believe these molecules 3-[(4-hydroxyphenyl)methyl]-6-(1H-indol-3-ylmethyl)piperazine-2,5-dione (ZINC04899565) and 1-[(3S)-3-[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyrrolidin-1-yl]ethanone (ZINC49171024) could be a starting point to help develop broad-spectrum antibiotics against infections caused by N. gonorrhoeae, A. baumannii, C. coli, K. pneumoniae, E. faecium, H. pylori, P. aeruginosa, S. aureus and S. typhi.
First record of Diaeretus leucopterus (Haliday) (Hymenoptera, Braconidae, Aphidiinae), the parasitoid of the aphid species, Eulachnus agilis (Kaltenbach) (Hemiptera, Aphididae) in North Africa
Authors: Ben Halima Kamel Monia , Kavallieratos Nickolas G. , Starý Petr , Rakhshani Ehsan
Published: May 2020

A survey of pine-associated aphids and their parasitoids was carried out in the arboretum ofPinus halepensisMiller in the Higher Agronomic Institute Chott Mariem (ISA CM, Tunisia) during 2010–2011 and 2018. The survey revealed the presence of the aphid parasitoid species,Diaeretus leucopterus(Haliday) (Hymenoptera, Braconidae, Aphidiinae). This is the first record ofD. leucopterusfrom Tunisia and the African continent. The parasitoid emerged from the spotted green pine needle aphid,Eulachnus agilis(Kaltenbach) (Hemiptera, Aphididae, Lachninae), onP. halepensis. The generalist hyperparasitoid,Asaphes suspensus(Nees) (Hymenoptera, Pteromalidae), was also found attackingD. leucopterus. The diagnosis of the primary parasitoid, on the basis of relevant illustrations, was provided, and the possible routes of its transportation into North Africa were discussed.
Percutaneous removal of air-bullet gunshot: case report and literature review
Authors: Alakhfash Ali A. , Alqwaee Abdullah , Almesned Abdulrahman
Published: May 2020

Background

Cardiac air bullet injuries are rare but can be associated with significant morbidity and mortality.

Case presentation

We are presenting a young male child who sustained an accidental injury to the chest by an air rifle. Bullet entered the right ventricle from the anterior part of the chest and was identified in the RV side of the interventricular septum by echocardiography and chest CT scan. There was mild pericardial effusion but no valvular injury. The bullet was removed in the cath lab, and the patient was discharged home on the second day.

Conclusions

It is reasonable to try foreign body removal in the cath lab, for certain cases, and avoid cardiac surgery.
Safe and informed prescribing of psychotropic medication during the COVID-19 pandemic
Authors: Luykx Jurjen J. , van Veen Sisco M. P. , Risselada Arne , Naarding Paul , Tijdink Joeri K. , Vinkers Christiaan H.
Published: May 2020

Treatment with psychotropic medication may sometimes be jeopardised because of the COVID-19 pandemic. One underlying reason is the lack of COVID-19-specific psychopharmacology guidelines. Here, we discuss five considerations arising from our clinical experience and pharmacological background knowledge to enable safe and well-informed psychopharmacotherapy during the COVID-19 pandemic.
Efficient and Accurate Extracting of Unstructured EHRs on Cancer Therapy Responses for the Development of RECIST Natural Language Processing Tools: Part I, the Corpus
Authors: Li Yalun , Luo Yung-Hung , Wampfler Jason A. , Rubinstein Samuel M. , Tiryaki Firat , Ashok Kumar , Warner Jeremy L. , Xu Hua , Yang Ping
Published: May 2020

PURPOSE

Electronic health records (EHRs) are created primarily for nonresearch purposes; thus, the amounts of data are enormous, and the data are crude, heterogeneous, incomplete, and largely unstructured, presenting challenges to effective analyses for timely, reliable results. Particularly, research dealing with clinical notes relevant to patient care and outcome is seldom conducted, due to the complexity of data extraction and accurate annotation in the past. RECIST is a set of widely accepted research criteria to evaluate tumor response in patients undergoing antineoplastic therapy. The aim for this study was to identify textual sources for RECIST information in EHRs and to develop a corpus of pharmacotherapy and response entities for development of natural language processing tools.

METHODS

We focused on pharmacotherapies and patient responses, using 55,120 medical notes (n = 72 types) in Mayo Clinic’s EHRs from 622 randomly selected patients who signed authorization for research. Using the Multidocument Annotation Environment tool, we applied and evaluated predefined keywords, and time interval and note-type filters for identifying RECIST information and established a gold standard data set for patient outcome research.

RESULTS

Key words reduced clinical notes to 37,406, and using four note types within 12 months postdiagnosis further reduced the number of notes to 5,005 that were manually annotated, which covered 97.9% of all cases (n = 609 of 622). The resulting data set of 609 cases (n = 503 for training and n = 106 for validation purpose), contains 736 fully annotated, deidentified clinical notes, with pharmacotherapies and four response end points: complete response, partial response, stable disease, and progressive disease. This resource is readily expandable to specific drugs, regimens, and most solid tumors.

CONCLUSION

We have established a gold standard data set to accommodate development of biomedical informatics tools in accelerating research into antineoplastic therapeutic response.
Pathogenic Variants in CHEK2 Are Associated With an Adverse Prognosis in Symptomatic Early-Onset Breast Cancer
Authors: Greville-Heygate Stephanie L. , Maishman Tom , Tapper William J. , Cutress Ramsey I. , Copson Ellen , Dunning Alison M. , Haywood Linda , Jones Louise J. , Eccles Diana M.
Published: May 2020

PURPOSE

Checkpoint kinase 2 ( CHEK2) is frequently included in multigene panels. We describe the associated outcomes among carriers of CHEK2 pathogenic variants in young patients with symptomatic breast cancer.

PATIENTS AND METHODS

Participants (N = 2,344) in the Prospective Outcomes in Sporadic Versus Hereditary Breast Cancer study had a diagnosis of primary invasive breast cancer at age ≤ 40 years. Summary statistics were used to compare tumor characteristics among CHEK2+ carriers with those who were CHEK2−. Kaplan-Meier curves were used to demonstrate overall survival (OS) and distant disease-free survival.

RESULTS

Overall, 53 of the 2,344 participants (2.3%) had a pathogenic CHEK2 variant. CHEK2+-associated tumors were significantly more likely to be grade 2, estrogen receptor and progesterone receptor–positive compared with CHEK2− tumors (grade 2, n = 28 of 52 [53.8%] v n = 803 of 2,229 [36.0%]; P = .029). CHEK2-associated tumors were significantly more likely to have nodal involvement (N1, n = 37 of 53 [69.8%] v 1,169 of 2,253 [51.9%]; P = .0098) and demonstrated a trend toward multifocality. A higher proportion of participants with CHEK2+ variants with invasive breast cancer were obese than were those with CHEK2− variant (28.3% v 18.8%; P = .039). Univariate and multivariable analyses revealed that OS and distant disease-free survival were significantly worse in CHEK2+ versus CHEK2− carriers (OS hazard ratio, 1.58; 95% CI, 1.01 to 2.48; P = .043).

CONCLUSION

This work highlights the adverse prognosis associated with breast cancer in carriers of CHEK2 pathogenic variants. It also identifies a potential association among obesity, family history, and breast cancer risk in young CHEK2 gene carriers.
Selective Progesterone Receptor Modulators—Mechanisms and Therapeutic Utility
Authors: Islam Md Soriful , Afrin Sadia , Jones Sara Isabel , Segars James
Published: May 2020

Selective progesterone receptor modulators (SPRMs) are a new class of compounds developed to target the progesterone receptor (PR) with a mix of agonist and antagonist properties. These compounds have been introduced for the treatment of several gynecological conditions based on the critical role of progesterone in reproduction and reproductive tissues. In patients with uterine fibroids, mifepristone and ulipristal acetate have consistently demonstrated efficacy, and vilaprisan is currently under investigation, while studies of asoprisnil and telapristone were halted for safety concerns. Mifepristone demonstrated utility for the management of endometriosis, while data are limited regarding the efficacy of asoprisnil, ulipristal acetate, telapristone, and vilaprisan for this condition. Currently, none of the SPRMs have shown therapeutic success in treating endometrial cancer. Multiple SPRMs have been assessed for efficacy in treating PR-positive recurrent breast cancer, with in vivo studies suggesting a benefit of mifepristone, and multiple in vitro models suggesting the efficacy of ulipristal acetate and telapristone. Mifepristone, ulipristal acetate, vilaprisan, and asoprisnil effectively treated heavy menstrual bleeding (HBM) in patients with uterine fibroids, but limited data exist regarding the efficacy of SPRMs for HMB outside this context. A notable class effect of SPRMs are benign, PR modulator-associated endometrial changes (PAECs) due to the actions of the compounds on the endometrium. Both mifepristone and ulipristal acetate are effective for emergency contraception, and mifepristone was approved by the US Food and Drug Administration (FDA) in 2012 for the treatment of Cushing’s syndrome due to its additional antiglucocorticoid effect. Based on current evidence, SPRMs show considerable promise for treatment of several gynecologic conditions.
The Changing Face of Adrenoleukodystrophy
Authors: Zhu Jia , Eichler Florian , Biffi Alessandra , Duncan Christine N , Williams David A , Majzoub Joseph A
Published: May 2020

Adrenoleukodystrophy (ALD) is a rare X-linked disorder of peroxisomal oxidation due to mutations in ABCD1. It is a progressive condition with a variable clinical spectrum that includes primary adrenal insufficiency, myelopathy, and cerebral ALD. Adrenal insufficiency affects over 80% of ALD patients. Cerebral ALD affects one-third of boys under the age of 12 and progresses to total disability and death without treatment. Hematopoietic stem cell transplantation (HSCT) remains the only disease-modifying therapy if completed in the early stages of cerebral ALD, but it does not affect the course of adrenal insufficiency. It has significant associated morbidity and mortality. A recent gene therapy clinical trial for ALD reported short-term MRI and neurological outcomes comparable to historical patients treated with HSCT without the associated adverse side effects. In addition, over a dozen states have started newborn screening (NBS) for ALD, with the number of states expecting to double in 2020. Genetic testing of NBS-positive neonates has identified novel variants of unknown significance, providing further opportunity for genetic characterization but also uncertainty in the monitoring and therapy of subclinical and/or mild adrenal insufficiency or cerebral involvement. As more individuals with ALD are identified at birth, it remains uncertain if availability of matched donors, transplant (and, potentially, gene therapy) centers, and specialists may affect the timely treatment of these individuals. As these promising gene therapy trials and NBS transform the clinical management and outcomes of ALD, there will be an increasing need for the endocrine management of presymptomatic and subclinical adrenal insufficiency. (Endocrine Reviews 41: 1 – 17, 2020)
The Rho guanine nucleotide exchange factor Trio is required for neural crest cell migration and interacts with Dishevelled
Authors: Kratzer Marie-Claire , Becker Sarah F. S. , Grund Anita , Merks Anne , Harnoš Jakub , Bryja Vítězslav , Giehl Klaudia , Kashef Jubin , Borchers Annette
Published: May 2020

Directional migration during embryogenesis and tumor progression faces the challenge that numerous external signals need to converge to precisely control cell movement. The Rho guanine exchange factor (GEF) Trio is especially well suited to relay signals as it features distinct catalytic domains to activate Rho GTPases. Here we show that Trio is required for Xenopus cranial neural crest (NC) cell migration and cartilage formation. Trio cell-autonomously controls protrusion formation of NC cells and Trio morphant NC cells show a blebbing phenotype. Interestingly, the Trio GEF2 domain is sufficient to rescue protrusion formation and migration of Trio morphant NC cells. We show that this domain interacts with the DEP/C-terminus of Dishevelled (DVL). DVL – but not a deletion construct lacking the DEP domain – is able to rescue protrusion formation and migration of Trio morphant NC cells. This is likely mediated by activation of Rac1, as we find that DVL rescues Rac1 activity in Trio morphant embryos. Thus, our data provide evidence for a novel signaling pathway, whereby Trio controls protrusion formation of cranial NC cells by interacting with DVL to activate Rac1.
Rspo2 antagonizes FGF signaling during vertebrate mesoderm formation and patterning
Authors: Reis Alice H. , Sokol Sergei Y.
Published: May 2020

R-spondins are a family of secreted proteins that play important roles in embryonic development and cancer. R-spondins have been shown to modulate the Wnt pathway, however their involvement in other developmental signaling processes have remained largely unstudied. Here we describe a novel function of Rspo2 in FGF pathway regulation in vivo. Overexpressed Rspo2 inhibited elongation of Xenopus ectoderm explants and Erk1 activation in response to FGF. By contrast, the constitutively active form of Mek1 stimulated Erk1 even in the presence of Rspo2, suggesting that Rspo2 functions upstream of Mek1. The observed inhibition of FGF signaling was accompanied by the dowregulation of the FGF target genes tbxt/brachyury and cdx4 that mediate anterioposterior axis specification. Importantly, these target genes were upregulated in Rspo2-depleted explants. The FGF inhibitory activity was mapped to the thrombospondin type 1 region (TSP), contrasting the known function of the Furin-like domains (FU) in Wnt signaling. Further domain analysis revealed an unexpected intramolecular interaction that may control Rspo2 signaling output. We conclude that, in addition to its role in Wnt signaling, Rspo2 acts as an FGF antagonist during mesoderm formation and patterning.
Body temperature stability observed in the whale sharks, the world's largest fish
Authors: Nakamura Itsumi , Matsumoto Rui , Sato Katsufumi
Published: May 2020

It is generally assumed that the body temperature of large animals is less likely to change due to their large body size, resulting in a high thermal inertia and a smaller surface area to volume ratio. The goal of this study was to investigate the stability of body temperature in large fish using data from field experiments. We measured the muscle temperatures of free-ranging whale sharks (Rhincodon typus), the largest extant fish globally, and investigated their ectothermic physiology and the stability of their body temperatures. The measured muscle temperature of the whale sharks changed substantially more slowly than the water temperature fluctuations associated with vertical movements, and the whole-body heat-transfer coefficients (HTC) of whale sharks estimated using heat-budget models were lower than those of any other fish species measured to date. The heat-budget models also showed that internal heat production does not contribute to changes in muscle temperature. A comparative analysis showed that the HTC at cooling in various fish species including both ectothermic and endothermic species ranging from 10−4 to 103 kg was proportional to body mass−0.63. This allometry was present regardless of whether the fish were ectothermic or endothermic, and was an extension of the relationship observed in previous studies on small fish. Thus, large fish have the advantage of body temperature stability while moving in environments with large temperature variations. Our results suggest that the large body size of whale sharks aids in preventing a decrease in body temperature during deep excursions to more than 1000 m depths without high metabolic costs of producing heat.
Membrane peroxidation index and maximum lifespan are negatively correlated in fish of genus Nothobranchius
Authors: de Costa Jorge , Barja Gustavo , Almaida-Pagan Pedro F.
Published: May 2020

Lipid composition of cell membranes is linked to metabolic rate and lifespan in mammals and birds but very little information is available for fishes. In this study, three fish species of the short-lived annual genus Nothobranchius with different maximum lifespan potentials (MLSP) and the longer-lived outgroup species Aphyosemion australe were studied to test whether they conform to the predictions of the longevity-homeoviscous adaptation (LHA) theory of aging. Lipid analyses were performed in whole fish samples and peroxidation indexes (PIn) for every PL class and for the whole membrane, were calculated. Total PL content was significantly lower in A. australe and N. korthausae, the two species with the highest MLSP, and a negative correlation between membrane total PIn and fish MLSP was found, this meaning that the longer-lived fish species have more saturated membranes and therefore, a lower susceptibility to oxidative damage, as the LHA theory posits.
Whale sharks increase swimming effort while filter feeding, but appear to maintain high foraging efficiencies
Authors: Cade David E. , Levenson J. Jacob , Cooper Robert , de la Parra Rafael , Webb D. Harry , Dove Alistair D. M.
Published: May 2020

Whale sharks (Rhincodon typus Smith 1828) – the largest extant fish species – reside in tropical environments, making them an exception to the general rule that animal size increases with latitude. How this largest fish thrives in tropical environments that promote high metabolism but support less robust zooplankton communities has not been sufficiently explained. We used open-source inertial measurement units (IMU) to log 397 hours of whale shark behavior in Yucatan, Mexico, at a site of both active feeding and intense wildlife tourism. Here we show that the strategies employed by whale sharks to compensate for the increased drag of an open mouth are similar to ram-feeders five orders of magnitude smaller and one order of magnitude larger. Presumed feeding constituted 20% of the total time budget of four sharks, with individual feeding bouts lasting up to 11 consecutive hrs. Compared to normal, sub-surface swimming, three sharks increased their stroke rate and amplitude while surface feeding, while one shark that fed at depth did not demonstrate a greatly increased energetic cost. Additionally, based on time-depth budgets, we estimate that aerial surveys of shark populations should consider including a correction factor of 3 to account for the proportion of daylight hours that sharks are not visible at the surface. With foraging bouts generally lasting several hours, interruptions to foraging during critical feeding periods may represent substantial energetic costs to these endangered species, and this study presents baseline data from which management decisions affecting tourist interactions with whale sharks may be made.
Secondary osteon structural heterogeneity between the cranial and caudal cortices of the proximal humerus in white-tailed deer
Authors: Nguyen Jack , Barak Meir M.
Published: May 2020

Cortical bone remodeling is an ongoing process triggered by microdamage, where osteoclasts resorb existing bone and osteoblasts deposit new bone in the form of secondary osteons (Haversian systems). Previous studies revealed regional variance in Haversian systems structure and possibly material, between opposite cortices of the same bone. As bone mechanical properties depend on tissue structure and material, it is predicted that bone mechanical properties will vary in accordance with structural and material regional heterogeneity. To test this hypothesis, we analyzed the structure, mineral content and compressive stiffness of secondary bone from the cranial and caudal cortices of the white-tailed deer proximal humerus. We found significantly larger Haversian systems and canals in the cranial cortex but no significant difference in mineral content between the two cortices. Accordingly, we found no difference in compressive stiffness between the two cortices and thus our working hypothesis was rejected. Seeing that the deer humerus is curved and thus likely subjected to bending during habitual locomotion, we expect that similar to other curved long bones, the cranial cortex of the deer humerus is likely subjected primarily to tensile strains and the caudal cortex is likely subject primarily to compressive strains. Consequently, our results suggest that strain magnitude (larger in compression) and sign (compression vs. tension) affect differently the osteoclasts and osteoblasts in the BMU. Our results further suggest that osteoclasts are inhibited in regions of high compressive strains (creating smaller Haversian systems) while osteoblasts’ osteoid deposition and mineralization is not affected by strain magnitude and sign.
A desigualdade econômica e a isonomia: uma reflexão sobre os perfis das desigualdades
Authors: Sampaio Ferraz Junior Tercio
Published: May 2020

Economic inequality and isonomia: a reflection on the profiles of inequalitiesRESUMOA Constituição Federal tem na igualdade um de seus núcleos basilares. Porém, é particularmente significativa a questão da desigualdade econômica. É esse “jogo” entre a igualdade de direito e a desigualdade de fato, pela percepção das diferenças, uma das questões cruciais de nossa era. Entender como se configura o perfil da igualdade/desigualdade econômica parece uma tarefa simples, mas é merecedora de uma reflexão. Esse questionamento é abordado, historicamente, no artigo em tela, à luz de Stiglitz, Huntington, Bienveniste, Arendt, Marx e Hegel, o que evocauma complicada relação entre política, direito e economia em que a desigualdade socioeconômica adquire um relevo ímpar. Em suma, é esse tema em toda sua complexidade que se torna o ponto crucial para os paradigmas clássicos na configuração de regimes políticos em termos de estado de direito.ABSTRACTThe Federal Constitution has equality one of its basic nucleus. However, the issue of economic inequality is particularly significant. It is this “game” between equality of law and inequality in fact, by the perception of differences, one of the crucial issues of our era. Understanding how the profile of equality/economic inequality is configured seems a simple task, but it is deserving of a reflection. This question is historically addressed in the screen article, in the light of Stiglitz, Huntington, Bienveniste, Arendt, Marx e Hegel which evokes a complicated relationship between politics, rights and economy in which socioeconomic inequality acquires an unmatched relief. In short, it is this theme in all its complexity that becomes the crucial point for classical paradigms in the configuration of political regimes in terms of State of Law.
Reparação e sanção no controle de atos e contratos administrativos: as diferentes formas de responsabilização pelo Tribunal de Contas
Authors: Heller Gabriel , Cavichioli Carmona Paulo Afonso
Published: May 2020

Restitution and punishment in the control of administrative acts and contracts: the different forms of liability by the Court of AccountsRESUMOO presente artigo diferencia as duas formas de responsabilização pelo Tribunal de Contas no controle dos atos e contratos administrativos: a condenação ao ressarcimento ao erário e a aplicação de sanções. A partir de pesquisa bibliográfica e documental, incluindo legislação e jurisprudência, atribui-se à primeira uma natureza financeiro-civil, da qual decorre um regime jurídico próprio com influxos do direito civil. Já no caso da aplicação de penalidades, defende-se que as sanções a cargo do controle externo têm natureza jurídica financeiro-administrativa e constituem um ramo autônomo do direito punitivo que compartilha, com o direito penal e o direito administrativo sancionador, uma origem constitucional comum,orientada para a proteção e a promoção dos direitos fundamentais.ABSTRACTThis paper aims to differentiate the two forms of liability by the Court of Accounts in the control of administrative acts and contracts: the order of restitution and the application of punishments. Based on bibliographical and documentary sources, including statutes and judicial rulings, we attribute a financial-civil nature to the former, resulting in a peculiar regulation of its own, influenced by civil law. Regarding the application of penalties, we argue that the external control sanctions have a financialadministrative legal nature and constitute an autonomous branch of punitive law that shares, with criminal law and sanctioning administrative law, a common constitutional origin, oriented for the protection and promotion of fundamental rights.
Measuring efficiency of Brazilian courts: one decade later
Authors: Yeung Luciana
Published: May 2020

Medindo a eficiência dos tribunais brasileiros: uma década depoisABSTRACTThe Judiciary is perhaps one of the most scrutinized political institutions in Brazil. Its credibility, independence and efficiency are considered to have crucial impacts on social, political and economic outcomes. This paper aims at measuring (in)efficiency of the Brazilian Judiciary and its dynamism in recent years (2009-2015). We use DEA (Data Envelopment Analysis) and the Malmquist index to evaluate efficiency and productivitychange in Brazilian courts. Our results show that, more than a decade after the Conselho Nacional de Justiça’s (CNJ) first attempts to publicize judicial statistics in the beginning of the year 2000, local courts have substantially improved the discipline and the quality of data production and collection. Yet, there is still much room for progress. In terms of productivity, the picture has not changed much; also, the Malmquist indexes showed little improvement throughout the years.RESUMOO Judiciário é, talvez, uma das instituições políticas mais escrutinadas no Brasil. Sua credibilidade, independência e eficiência têm impactos cruciais nos resultados sociais, políticos e econômicos. Este trabalho visa medir a (in)eficiência do Judiciário brasileiro e sua dinâmica nos últimos anos (2009-15). Utilizamos a Análise Envoltória de Dados — Data Envelopment Analysis (DEA) e o Índice de Malmquist para avaliar a eficiência e a mudança de produtividade nos tribunais. Nossos resultados mostram que, mais de uma década depois das primeiras divulgações de estatísticas pelo Conselho Nacional de Justiça (CNJ), os tribunais locais melhoraram substancialmente a disciplina e a qualidade da produção e coleta de dados. Mas há ainda muito espaço para progresso. Em termos de produtividade, a situação não mudou muito; também os Índices de Malmquist apresentaram pouca evolução ao longo dos anos.
O direito administrativo e sua contribuição no enfrentamento à corrupção
Authors: Shuenquener de Araújo Valter
Published: May 2020

Administrative law and its contribution in the fight against corruptionRESUMOEste texto tem como objetivo analisar de que forma o direito administrativo pode contribuir para reduzir os níveis de corrupção no Brasil. Ao ladodo direito penal, o direito administrativo pode ocupar um espaço valioso no combate a ilícitos que atingem os cofres públicos. Para tanto, é preciso que ocorram algumas mudanças estruturais na forma como o direito administrativo ainda compreende a relação jurídica entre o cidadão e o Estado. Desburocratização, incremento da transparência e uma maior racionalização do direito administrativo sancionador são medidas eficazes elencadas neste artigo que podem ser adotadas para o aprimoramento do enfrentamento estatal a práticas desonestas e corruptas. A metodologia utilizada será a bibliográfica e o objetivo da pesquisa será o de contribuir para a redução do problema da corrupção.ABSTRACTThis text intends to ascertain how Administrative Law can contribute to reduce the corruption levels in Brazil. In addition to Criminal Law, Administrative Law can also play a valuable role in the fight against illegal conducts that affect Public Administration. For that purpose, there must be some structural changes in the way the Administrative Law deals with the legal relationship between the citizen and the State. Debureaucratization, transparency increase and a greater rationalization of the Sanctioning Administrative Law are effective measures listed in this paper to befollowed to improve the way the state fights against dishonest and corrupt practices. The methodology adopted will be the bibliographical one and the research objective is to contribute to the reduction of the corruption problem.