bluuebunny/crossref_metadata_2025 huggingface dataset:
Controversial aspects of testosterone in the regulation of sexual function in late‐onset hypogonadism
Authors: Maggi Mario , Filippi Sandra , Vignozzi Linda , Rastrelli Giulia
Published: April 2020

Background

Testosterone (T) plays a pivotal role in coordinating a series of psychological, cognitive and physical events that might (or might not) culminate in male sexual activity. In fact, T deficiency is associated, in a statistically significant way, with several sexual dysfunctions including erectile dysfunction (ED), reduction of spontaneous erection and hypoactive sexual desire (HSD). Although these associations are statistically significant, there is debate if they are also clinically meaningful. In addition, sexual dysfunctions are present also in several metabolic conditions ‐ such as type 2 diabetes mellitus and obesity ‐ that often associate with low T. In particular, this is the case of ED, but not of HSD, that, therefore, should be considered a more genuine correlate of T deficiency in adulthood and aging (late‐onset hypogonadism, LOH).

Objectives

The aim of this review is to scrutinize evidence from our and other studies on sexual effects of T replacement therapy (TRT) in LOH.

Materials and methods

We will use preclinical and clinical data coming from our and other laboratories and meta‐analyses.

Results

Intervention studies in clinical trials involving subjects with LOH, and their meta‐analyses, indicate that TRT is able to ameliorate HSD, spontaneous erection and ED. However, the relative improvement of ED by TRT is marginal [2‐3 points of International Index of Erectile Function‐erectile function domain (IIEF‐EFD)] and significantly smoothed in subjects with the aforementioned metabolic conditions. In LOH, positive effects of TRT on other domains of sexual activity, such as orgasm and sexual satisfaction, are also apparent in the different meta‐analyses.

Discussion and conclusions

Hence, TRT is a reasonable treatment for restoring sexual drive in LOH, with some additional positive effects also on erection (spontaneous and sexual‐related) and on orgasm. In contrast, preclinical and clinical studies indicate that T administration to eugonadal subjects does not improve male sexual activity.
Retinal oximetry in glaucoma: investigations and findings reviewed
Authors: Shughoury Aumer , Mathew Sunu , Arciero Julia , Wurster Patrick , Adjei Susuana , Ciulla Thomas , Siesky Brent , Harris Alon
Published: April 2020

Abnormalities of the retinal blood supply have been widely implicated in primary open‐angle glaucoma (POAG). Impaired blood supply to the retina and optic nerve head (ONH) may be a primary pathophysiologic mechanism contributing to POAG (‘vascular hypothesis’). However, the decreased metabolic activity of atrophic tissue is itself known to induce both vascular changes and decreased blood flow due to reduced oxygen demand. Therefore, primary nonvascular factors could potentially induce glaucomatous atrophy, with subsequent secondary vascular pathology (‘mechanical hypothesis’). Retinal oximetry holds great promise in the investigation of glaucoma pathogenesis, as it can provide useful data on retinal metabolic oxygen demand, especially when combined with measurements of retinal blood flow. This review surveys the research on retinal metabolism in POAG using spectroscopic retinal oximetry. The use of mathematical models in combination with oximetric data to investigate the role of retinal metabolism and oxygen supply in POAG is also discussed.
Interactions between ocular and systemic disease using national register‐based data in the Danish Excellence Centre in Ophthalmic Epidemiology (DECODE‐EYE): study perspective
Authors: Grauslund Jakob , Stokholm Lonny , Ohm Kyvik Kirsten , Dornonville de la Cour Morten , Kessel Line , Hass Rubin Katrine
Published: April 2020

Purpose

The Danish Excellence Centre in Ophthalmic Epidemiology (DECODE‐EYE) is a national research collaboration formed in order to study the real‐life interaction between ocular and systemic disease based on the entire Danish population. Here, we aim to describe the study design and the methodology, which will be used.

Methods

We will extract data from various healthcare registers and databases including the Danish Civil Registration System (unique personal identifier), the Danish National Patient Register (inpatient and outpatient visits), the Danish National Prescription Registry (redeemed prescription drugs), the National Health Service Register (data on health services in primary health care), the Danish Register of Cause of Death (data on cause of death), Statistics Denmark (demographic and socioeconomic data), the Danish Registry of Diabetic Retinopathy (level of diabetic retinopathy (DR) in diabetes patients) and the database of the Danish Association of the Blind (date and cause of blindness). Relevant registers will be linked by the unique personal identifier, and associations will be examined cross‐sectional and/or longitudinally, in principle in 1:5 age‐ and gender‐matched case–control cohort studies.

Conclusion

Denmark has a strong tradition in register‐based healthcare research, given a high number of validated national registers and databases. DECODE‐EYE will provide Danish, large‐scale data on associations between ocular and systemic disease.

With a target population of 5.8 million individuals, twelve separate studies (Protocols A–L) have initially been designed to be studied in the upcoming years. These will provide novel data on interactions between systemic disease and relevant ophthalmological end‐points like blindness, DR, glaucoma, corneal disease, retinal vascular disease, cataract and intravitreal angiostatic treatment.
Propofol in neonates causes a dose‐dependent profound and protracted decrease in blood pressure
Authors: de Kort Ellen H. M. , Twisk Jos W. R. , van t Verlaat Ellen P. G. , Reiss Irwin K. M. , Simons Sinno H. P. , van Weissenbruch Mirjam M.
Published: April 2020

Aim

To analyse the effects of different propofol starting doses as premedication for endotracheal intubation on blood pressure in neonates.

Methods

Neonates who received propofol starting doses of 1.0 mg/kg (n = 30), 1.5 mg/kg (n = 23) or 2.0 mg/kg (n = 26) as part of a previously published dose‐finding study were included in this analysis. Blood pressure in the 3 dosing groups was analysed in the first 60 minutes after start of propofol.

Results

Blood pressure declined after the start of propofol in all 3 dosing groups and was not restored 60 minutes after the start of propofol. The decline in blood pressure was highest in the 2.0 mg/kg dosing group. Blood pressure decline was mainly dependent on the initial propofol starting dose rather than the cumulative propofol dose.

Conclusion

Propofol causes a dose‐dependent profound and prolonged decrease in blood pressure. The use of propofol should be carefully considered. When using propofol, starting with a low dose and titrating according to sedative effect seems the safest strategy.
Death‐scene investigations contribute to legal protection in unexpected child deaths in Norway
Authors: Bøylestad Lillian , Stray‐Pedersen Arne , Vege Åshild , Osberg Silje , Rognum Torleiv
Published: April 2020

Aim

This study reviewed cases of sudden unexpected child deaths in Norway to determine the significance of death‐scene investigations (DSIs) in establishing cause and manner of death, and thereby it is relevance to legal protection.

Methods

Data from forensic autopsy reports and DSIs were collected and analysed for cases of unexpected deaths in children below 4 years of age in Norway during 2010‐2016.

Results

Out of 141 cases, the death scene was investigated as a voluntary procedure in 75 cases and by the police in 41 cases. The cause of death remained unexplained in 81/141 (57%) of the cases, of which 46/141 (33%) met the criteria for sudden infant death syndrome (SIDS) or sudden unexplained death in early childhood (SUDC). The manner of death was determined in 102/141 (72%). Voluntary DSI increased the ability to rule out accidental suffocation, facilitated evaluations of environmental risk factors and enabled detection of possible neglect.

Conclusion

Death‐scene investigations illuminate uncertainty about the cause of death, especially in grey‐area cases where accidental suffocation, neglect or abuse is suspected. Knowledge about the course of events and the cause of death enhances both the child's and the caregiver's legal protection. Death‐scene investigations should therefore be mandatory.
Absorption, distribution, metabolism and excretion of molidustat in healthy participants
Authors: Lentini Silvia , van der Mey Dorina , Kern Armin , Thuss Uwe , Kaiser Andreas , Matsuno Kumi , Gerisch Michael
Published: April 2020

The absorption, distribution, metabolism and excretion of molidustat were investigated in healthy male participants. In study 1, a mass balance study, radiolabelled molidustat 25 mg (3.57 MBq) was administered as an oral solution (n = 4). Following rapid absorption, molidustat‐related radioactivity was predominantly distributed in plasma rather than in red blood cells. The total recovery of the administered radioactivity was 97.0%, which was mainly excreted renally (90.7%). Metabolite M‐1, produced by N‐glucuronidation, was the dominant component in plasma (80.2% of the area under the concentration‐time curve for total radioactivity) and was primarily excreted via urine (~85% of dose). Only minor amounts of unchanged molidustat were excreted in urine (~4%) and faeces (~6%). Study 2 investigated the absolute bioavailability and pharmacodynamics of molidustat (part 1, n = 12; part 2, n = 16). Orally administered molidustat immediate release tablets had an absolute bioavailability of 59%. Following intravenous administration (1, 5 and 25 mg), total body clearance of molidustat was 28.7‐34.5 L/h and volume of distribution at steady state was 39.3‐50.0 L. All doses of molidustat transiently elevated endogenous erythropoietin levels, irrespective of the route of administration. Molidustat was considered safe and well tolerated at the administered doses.
Coordinating learning analytics policymaking and implementation at scale
Authors: Broos Tom , Hilliger Isabel , Pérez-Sanagustín Mar , Htun Nyi‐Nyi , Millecamp Martijn , Pesántez-Cabrera Paola , Solano‐Quinde Lizandro , Siguenza‐Guzman Lorena , Zuñiga‐Prieto Miguel , Verbert Katrien , De Laet Tinne
Published: April 2020

Many Latin‐American institutions recognise the potential of learning analytics (LA). However, the number of actual LA implementations at scale remains limited, notwithstanding considerable effort made to formulate guidelines and frameworks to support the LA policy development. Guidance on how to coordinate the interaction between the LA policymaking and implementation is mostly missing, leaving a difficult challenge up to practitioners. In this study we propose a coordination model to support future LA initiatives at scale. We explore the problem by comparing two cases in Belgium and Ecuador. Following up we use the LA implementation timeline as a driver for planning the interaction between the policymaking and implementation. We continue by testing an application of the model with LA experts predominantly from Latin‐American institutions, asking them to map low‐level items of the SHEILA policy framework to four implementation phases. The results of this mapping support that LA policy building can be spread over time, that it can coincide with LA implementation at scale, and that both efforts can be coordinated. It is hoped that this study will provide additional guidance for future Latin‐American and other LA initiatives.
Escape boxes: Bringing escape room experience into the classroom
Authors: Veldkamp Alice , Daemen Joke , Teekens Stijn , Koelewijn Stefan , Knippels Marie‐Christine P. J. , van Joolingen Wouter R.
Published: April 2020

In this paper, we present an escape box as a means to introduce the escape room concept into classrooms. Recreational escape rooms have inspired teachers all over the world to adapt the popular entertainment activity for education. Escape rooms are problem‐based and time‐constrained, requiring active and collaborative participants, a setting that teachers want to achieve in their classroom to promote learning. This paper explores the adaptation of the escape room concept into educational escape game boxes. These technology‐enhanced escape boxes have become hybrid learning spaces, merging individual and collaborative learning, as well as physical and digital spaces. The design of the box with assignments on each side puts users face to face with each other and requires them to collaborate in the physical world, instead of being individually absorbed in a digital world. The developed box is a unique concept in the field of escape rooms; the content is adaptable. This paper describes the process leading to the design criteria, the design process, test results and evaluation, and provides recommendations for designing educational escape rooms.
Single‐port robot‐assisted radical prostatectomy: a systematic review and pooled analysis of the preliminary experiences
Authors: Checcucci Enrico , De Cillis Sabrina , Pecoraro Angela , Peretti Dario , Volpi Gabriele , Amparore Daniele , Piramide Federico , Piana Alberto , Manfredi Matteo , Fiori Cristian , Autorino Riccardo , Dasgupta Prokar , Porpiglia Francesco ,   the Uro‐technology and SoMe Working Group of the Young Academic Urologists Working Party of the European Association of urology
Published: April 2020

Objective

To summarize the clinical experiences with single‐port (SP) robot‐assisted radical prostatectomy (RARP) reported in the literature and to describe the peri‐operative and short‐term outcomes of this procedure.

Material and Methods

A systematic review of the literature was performed in December 2019 using Medline (via PubMed), Embase (via Ovid), Cochrane databases, Scopus and Web of Science (PROSPERO registry number 164129). All studies that reported intra‐ and peri‐operative data on SP‐RARP were included. Cadaveric series and perineal or partial prostatectomy series were excluded.

Results

The pooled mean operating time, estimated blood loss, length of hospital stay and catheterization time were 190.55 min, 198.4 mL, 1.86 days and 8.21 days, respectively. The pooled mean number of lymph nodes removed was 8.33, and the pooled rate of positive surgical margins was 33%. The pooled minor complication rate was 15%. Only one urinary leakage and one major complication (transient ischaemic attack) were recorded. Regarding functional outcomes, pooled continence and potency rates at 12 weeks were 55% and 42%, respectively.

Conclusions

The present analysis confirms that SP‐RARP is safe and feasible. This novel robotic platform resulted in similar intra‐operative and peri‐operative outcomes to those obtained with the standard multiport da Vinci system. The advantages of single incision can be translated into a preservation of the patient’s body image and self‐esteem and cosmesis, which have a great impact on a patient's quality of life.
Overexpression of miR‐199/214 is a distinctive feature of iron‐induced and asbestos‐induced sarcomatoid mesothelioma in rats
Authors: Okazaki Yasumasa , Chew Shan Hwu , Nagai Hirotaka , Yamashita Yoriko , Ohara Hiroki , Jiang Li , Akatsuka Shinya , Takahashi Takashi , Toyokuni Shinya
Published: April 2020

Malignant mesothelioma (MM) is one of the most lethal tumors in humans. The onset of MM is linked to exposure to asbestos, which generates reactive oxygen species (ROS). ROS are believed to be derived from the frustrated phagocytosis and the iron in asbestos. To explore the pathogenesis of MM, peritoneal MM was induced in rats by the repeated intraperitoneal injection of iron saccharate and nitrilotriacetate. In the present study, we used microarray techniques to screen the microRNA (miR) expression profiles of these MM. We observed that the histological subtype impacted the hierarchical clustering of miR expression profiles and determined that miR‐199/214 is a distinctive feature of iron saccharate‐induced sarcomatoid mesothelioma (SM). Twist1, a transcriptional regulator of the epithelial‐mesenchymal transition, has been shown to activate miR‐199/214 transcription; thus, the expression level of Twist1 was examined in iron‐induced and asbestos‐induced mesotheliomas in rats. Twist1 was exclusively expressed in iron saccharate‐induced SM but not in the epithelioid subtype. The Twist1‐miR‐199/214 axis is activated in iron saccharate‐induced and asbestos‐induced SM. The expression levels of miR‐214 and Twist1 were correlated in an asbestos‐induced MM cell line, suggesting that the Twist1‐miR‐199/214 axis is preserved. MeT5A, an immortalized human mesothelial cell line, was used for the functional analysis of miR. The overexpression of miR‐199/214 promoted cellular proliferation, mobility and phosphorylation of Akt and ERK in MeT5A cells. These results indicate that miR‐199/214 may affect the aggressive biological behavior of SM.
Corrected human papillomavirus vaccination rates for each birth fiscal year in Japan
Authors: Nakagawa Satoshi , Ueda Yutaka , Yagi Asami , Ikeda Sayaka , Hiramatsu Kosuke , Kimura Tadashi
Published: April 2020

In Japan, the serious adverse events after human papillomavirus (HPV) vaccination were widely reported in the media. The Ministry of Health, Labour and Welfare of Japan (MHLW) announced the suspension of the governmental recommendation of HPV vaccine in 2013, and the inoculation rate has since sharply declined. The estimated inoculation rate for each birth fiscal year (FY) announced by the MHLW and the actual numbers for each birth FY surveyed by local governments were very different. In particular, the cumulative vaccination rate of girls born in FY2000 was regarded to be as high as 42.9% by the Council of the MHLW. However, this estimation included a confusion. When the suspension of the governmental recommendation was announced in FY2013, the girls born in FY2000 turned 13 years old, the targeted starting age of the HPV vaccination. The vaccination rate of this generation is considered to be quite low. The numbers were recalculated in this study. This study revealed that the real vaccination rate is only 14.3%. Female individuals born in or after FY2000 have been confirmed to be exposed to the same cervical cancer risk as before the HPV vaccine was introduced in Japan.
Acquired resistance to trastuzumab/pertuzumab or to T‐DM1 in vivo can be overcome by HER2 kinase inhibition with TAS0728
Authors: Irie Hiroki , Kawabata Rumi , Fujioka Yayoi , Nakagawa Fumio , Itadani Hiraku , Nagase Hideki , Ito Kimihiro , Uchida Junji , Ohkubo Shuichi , Matsuo Kenichi
Published: April 2020

HER2‐targeting antibodies (trastuzumab, pertuzumab) and a HER2‐directed antibody‐drug conjugate (trastuzumab emtansine: T‐DM1) are used for the treatment of HER2‐overexpressing breast cancer. However, these treatments eventually become ineffective due to acquired resistance and there is an urgent need for alternative therapies. TAS0728 is a small‐molecule, irreversible selective HER2 kinase inhibitor. In the present study, we established new in vivo models of cancer resistance by continuous exposure to a combination of trastuzumab and pertuzumab or to T‐DM1 for evaluating the effect of TAS0728 on HER2 antibody‐resistant populations. Treatment with trastuzumab and pertuzumab or with T‐DM1 initially induced tumor regression in NCI‐N87 xenografts. However, tumor regrowth during treatment indicated loss of drug effectiveness. In tumors with acquired resistance to trastuzumab and pertuzumab or to T‐DM1, HER2‐HER3 phosphorylation was retained. Switching to TAS0728 resulted in a significant anti‐tumor effect associated with HER2‐HER3 signal inhibition. No alternative receptor tyrosine kinase activation was observed in these resistant tumors. Furthermore, in a patient‐derived xenograft model derived from breast cancer refractory to both trastuzumab/pertuzumab and T‐DM1, TAS0728 exerted a potent anti‐tumor effect. These results suggest that tumors with acquired resistance to trastuzumab and pertuzumab and to T‐DM1 are still dependent on oncogenic HER2‐HER3 signaling and are vulnerable to HER2 signal inhibition by TAS0728. These results provide a rationale for TAS0728 therapy for breast cancers that are refractory to established anti‐HER2 therapies.
OTU deubiquitinase 5 inhibits the progression of non‐small cell lung cancer via regulating p53 and PDCD5
Authors: Kang Xiao‐yun , Zhang Jing , Tang Ling , Huang Liu , Tong Jin , Fu Qiang
Published: April 2020

Non‐small cell lung cancer (NSCLC) has the highest morbidity and mortality worldwide. OTU deubiquitinase 5 (OTUD5), a deubiquitinating enzyme, can enhance the stability of p53 and programmed cell death 5 (PDCD5), a protein related to the apoptosis, by deubiquitination. This study aimed to explore the biological function and underlying mechanism of OTUD5 in NSCLC. Western blot and qRT‐PCR were used to detect the expression of OTUD5 protein and mRNA in NSCLC tissues and cells, respectively. RNAi was adopted to construct an OTUD5 low‐expression model while the plasmids overexpressing p53 and PDCD5 were used to establish the overexpression models, respectively. CCK‐8 assay, transwell assay, and apoptosis assay were carried out to analyze the changes in the proliferation, migration, and chemoresistance of A549 and HCC827 cells. The mechanism of OTUD5 in NSCLC was studied by Western blot. Down‐regulated OTUD5 in NSCLC tissues was significantly correlated to a poor prognosis. The knockdown of OTUD5 inactivated p53 and PDCD5, promoting the proliferation and metastasis of NSCLC cells while inhibiting their apoptosis. OTUD5 knockdown also enhanced the resistance of NSCLC cells to doxorubicin and cisplatin. OTUD5 acted as a tumor suppressor in NSCLC by regulating the p53 and PDCD5 pathways.
The Development of a Scarcity Bias
Authors: Ferera Matar , Benozio Avi , Diesendruck Gil
Published: April 2020

Adults’ attraction to rare objects has been variously attributed to fundamental biases related to resource availability, self‐related needs, or beliefs about social and market forces. The current three studies investigated the scarcity bias in 11‐ and 14‐month‐old infants, and 3‐ to 6‐year‐old children (N = 129). With slight methodological modifications, participants had to choose between one of 10 same‐kind‐items (abundant resource), or the only one of a different kind (scarce resource). It was found that a robust preference for the scarce resource appeared only at age 5 years. Thus, although a scarcity bias is not present in infancy, it emerges prior to comprehension of market forces. Possible accounts of this developmental finding are discussed.
Differentiated thyroid cancer mortality by disease stage in northern England
Authors: Perros Petros , Mason David , Pearce Mark , Pearce Simon H. S. , Chandler Robert , Mallick Ujjal K.
Published: April 2020

Objective

Mortality from thyroid cancer is reported to be higher in the UK compared with several other European countries, though UK data on mortality by disease stage have not been published. The aim of this study was to ascertain disease‐specific mortality by stage in our centre.

Design, patients and measurements

This was a cohort study of all patients presenting to a single centre. Four hundred and twenty patients treated between 2000 and 2010 were identified. The medical records and causes of deaths were reviewed and analysed.

Results

Overall disease‐specific mortality at 5 and 10 years was 1.4% and 5.8%, respectively. The observed mortality was 58 against 66.3 expected deaths (CI 43.8‐75.4) thus yielding an age‐standardized mortality rate of 0.87. There were no deaths due to thyroid cancer in patients with stage I disease at 5 or 10 years. The 10‐year disease‐specific mortality rose with stage (stage II 3.1%, stage III 28.6%, stage IV 30%).

Conclusions

Thyroid cancer mortality of patients treated at our centre was lower than the official national UK registry and most European figures.
Reconciling care and justice in contesting social harm through performance and arts practice with looked after children and care leavers
Authors: Benaton Tonimarie , Bowers‐Brown Tamsin , Dodsley Thomas , Manning‐Jones Alix , Murden Jade , Nunn Alexander ,   The Plus One Community
Published: April 2020

The proportion of young people taken into the care of the state has increased recently and there is evidence that this social group suffer negative long‐term outcomes that might be conceptualised by the emergent criminological category of ‘social harm’. Debates in social work around an ethics of care and justice offer different ways of thinking about responding to social harm. This paper reports findings from an innovative arts‐based intervention with Looked After Children and young people and concludes that holding these competing value sets in creative tension is central to the success of the programme in helping young people to cope with and contest social harm.
Household behavior with respect to meat consumption in the presence of BSE and CWD
Authors: Myae Aye Chan , Goddard Ellen
Published: April 2020

In this study, Canadian household meat consumption behavior in exotic (deer and elk meat) and traditional meats (beef, pork, chicken, turkey, bison, and seafood) is examined. This research introduces some differences in public response to transmissible spongiform encephalopathies (TSE) risks across consumer segments from different sources of meat supply, including hunted meat. The analysis uses a combination of survey and household meat purchase data that include a balanced household panel of 2,393 households per year across time. A two‐step estimation procedure is used with a probit model in the first step (consume or not) and a doublelog–translog two‐stage demand system in the second step (level of consumption). It is assumed and tested that household sociodemographics, consumers’ risk perceptions/attitudes, and media coverage of bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD) are underlying demand shifters in consumers’ daily meat purchase decision. The results suggest that households who obtain venison from hunting show the highest confidence in venison safety. Exotic meat preferences negatively affect traditional meat consumption in the daily diets of households who purchase traditional meats from stores and obtain venison from hunting. In response to the media coverage of BSE and CWD, exotic meat eaters are less sensitive to animal disease media information than the general population.
Indium and iridium: Two rare metals with a high rate of contact sensitization
Authors: Terrani Isabella , Scherer Hofmeier Kathrin , Bircher Andreas J.
Published: April 2020

Background

Humans are exposed to a variety of metals on a daily basis, and nickel is the most frequent contact allergen. Little is known about the frequency of sensitization to indium and iridium.

Objectives

Study the prevalence of indium and iridium sensitization and evaluate the optimal patch test conditions.

Methods

A total of 364 patients were patch tested at the allergy unit of the University Hospital of Basel. Pure metals, metal chlorides, and metal sulfates were applied in petrolatum or water in Inert Quadrate (IQ) test chambers for 2 days and read twice at day (D) 2, and between D4 and D7.

Results

Eleven patients reacted to indium salts (3.0%), 13 to iridium salts (3.6%), and one reacted to both salts. None of the patients reacted to pure metals. Nineteen of the 23 patients who reacted either to indium or iridium showed concomitant positive reactions to other metals, mainly nickel and palladium.

Conclusion

This retrospective clinical study provides insight into the prevalence and test conditions of two rarely tested metal allergens in a large patient cohort. A considerable number of indium‐ or iridium‐positive subjects had co‐sensitization to other metals.
Natural ingredients in cosmetic products—A suggestion for a screening series for skin allergy
Authors: Bruusgaard‐Mouritsen Maria A. , Johansen Jeanne D. , Zachariae Claus , Kirkeby Christel S. , Garvey Lene H.
Published: April 2020

Background

Naturally derived cosmetic product ingredients of both plant and animal origin are being included increasingly in product formulations in order to cater to consumer preferences. They may be an overlooked cause of reactions to cosmetic products in some patients with dermatitis.

Objectives

To identify naturally derived cosmetic product ingredients with allergenic potential (type I and type IV) and propose a cosmetic screening test series.

Methods

The study was conducted in two steps. The first step was a market survey using a nonprofit application helping consumers avoid problematic substances in cosmetic products. The application contained 10 067 cosmetic products that were label checked for naturally derived cosmetic product ingredients. The second step was a literature search to examine how frequently the naturally derived ingredients were described and related to allergic reactions in cosmetics or other topically administered products.

Results

We identified 121 different naturally derived cosmetic product ingredients that were included in at least 30 cosmetic products. In total, 22 ingredients were selected for a screening test series.

Conclusions

We propose a supplemental patch test and a prick test screening series with naturally derived cosmetic product ingredients for patients with skin reactions to cosmetic products, aiming to identify a cause in more patients than is currently possible.
Clinical relevance of endoscopy with histopathological assessment in children with suspected gastrointestinal graft‐versus‐host disease
Authors: Mårtensson Thomas , Mellgren Karin , Toporski Jacek , Arvidson Johan , Szakos Attila , Casswall Thomas H. , Gustafsson Britt
Published: April 2020

Endoscopy with histopathological assessment is an established practice to confirm gastrointestinal graft‐versus‐host disease (GI‐GVHD). However, the clinical relevance of this approach in children is incompletely evaluated. In a retrospective cohort study, we investigated the frequency of treatment changes in response to histopathological findings in all children (<18 years) in Sweden who underwent endoscopy for suspected GI‐GVHD (2000‐2013) after receiving hematopoietic stem cell transplantation. Sixty‐eight children with ninety‐one endoscopic occasions were enrolled. At the time of endoscopy, anti‐GI‐GVHD treatment was ongoing in 71% (65/91). In 18% (12/65) with ongoing treatment, no histopathological evidence of GI‐GVHD or another cause to justify anti‐GI‐GVHD treatment was found. In 48% (44/91), endoscopy with histopathological assessment led to changes in the treatment regimen. Re‐endoscopy was more frequent among those with treatment changes, versus unchanged treatment, 39% (17/44) and 13% (6/47), respectively (P = .007). Histopathological findings generating treatment changes were as follows: GI‐GVHD in 68% (30/44), normal histology in 25% (11/44), and an alternative diagnosis in 7% (3/44). In conclusion, this study supports that endoscopy with histopathological assessment should be considered in all children with suspected GI‐GVHD.
Digital mucous cyst: Altered epidermal mucin as a clue to diagnosis
Authors: Moradi Sara , Ricci Andrew , Ehrig Torsten
Published: April 2020

Background

Digital mucous cyst (DMC) is histopathologically characterized by accumulation of mucin in the dermis. Some cases of DMC also show epidermal mucin, the histopathologic appearance and staining properties of which have not been described in detail.

Methods

A total of 24 cases of DMC were investigated by routine hematoxylin‐eosin (H&E) and Alcian blue stains in addition to AE1/AE3 immunohistochemistry.

Results

Nine out of the 24 cases of DMC showed epidermal mucin. As the epidermal mucin migrates upward within the epidermis, it transforms from a flocculent granular substance into one or several solid horizontal plugs with a more homogeneous appearance and incorporates cytoplasmic fragments of keratinocytes/corneocytes. The homogeneous mucin plugs stain eosinophilic or amphophilic with an H&E formulation using hematoxylin 7212 and basophilic with Gill 3 or Harris's hematoxylin. The eosinophilic staining is enhanced when the eosin solution contains phloxine.

Conclusions

The variably eosinophilic, amphophilic, or basophilic staining of epidermal mucin can be explained by its composition of basophilic mucin and eosinophilic debris from cytoplasmic fragments. The eosinophilic staining of mucin has not been reported before and can be diagnostically important because it may be mistaken for serum exudate.
Impact of image analysis and artificial intelligence in thyroid pathology, with particular reference to cytological aspects
Authors: Girolami Ilaria , Marletta Stefano , Pantanowitz Liron , Torresani Evelin , Ghimenton Claudio , Barbareschi Mattia , Scarpa Aldo , Brunelli Matteo , Barresi Valeria , Trimboli Pierpaolo , Eccher Albino
Published: April 2020

Objective

Thyroid pathology has great potential for automated/artificial intelligence algorithm application as the incidence of thyroid nodules is increasing and the indeterminate interpretation rate of fine‐needle aspiration remains relatively high. The aim of the study is to review the published literature on automated image analysis and artificial intelligence applications to thyroid pathology with whole‐slide imaging.

Methods

Systematic search was carried out in electronic databases. Studies dealing with thyroid pathology and use of automated algorithms applied to whole‐slide imaging were included. Quality of studies was assessed with a modified QUADAS‐2 tool.

Results

Of 919 retrieved articles, 19 were included. The main themes addressed were the comparison of automated assessment of immunohistochemical staining with manual pathologist's assessment, quantification of differences in cellular and nuclear parameters among tumour entities, and discrimination between benign and malignant nodules. Correlation coefficients with manual assessment were higher than 0.76 and diagnostic performance of automated models was comparable with an expert pathologist diagnosis. Computational difficulties were related to the large size of whole‐slide images.

Conclusions

Overall, the results are promising and it is likely that, with the resolution of technical issues, the application of automated algorithms in thyroid pathology will increase and be adopted following suitable validation studies.
Endoscopic ultrasound‐guided percutaneous endoscopic gastrostomy
Authors: Baile‐Maxía Sandra , Medina‐Prado Lucía , Bozhychko Maryana , Mangas‐Sanjuan Carolina , Ruiz Francisco , Compañy Luis , Martínez Juan , Antonio Casellas Juan , Aparicio José Ramón
Published: April 2020

Percutaneous endoscopic gastrostomy (PEG) is the method of choice for feeding and nutritional support in patients with a normal gastrointestinal function who require long‐term enteral nutrition. We report our experience regarding an alternative endoscopic ultrasound (EUS)‐guided PEG technique. A retrospective clinical experience case series study was conducted from January 2019 to November 2019 at a tertiary center. Adult patients deemed unfit for conventional PEG due to absence of transillumination or previous gastric surgery were enrolled. An EUS target was created by filling a glove with saline and placing it in the abdomen. EUS was performed and the target identified from the stomach. The abdominal wall was punctured from the stomach and a guidewire was advanced. The guidewire was knotted to a string, which was passed into the stomach and drawn back through the mouth. The procedure was continued following the traditional technique. Four patients underwent EUS‐PEG in our center during the study period. Mean age was 65 years and 50% were male. Two patients (50%) had a body mass index over 30. PEG indications were tongue malignancies (50%), cerebrovascular disease (25%) and dementia (25%). One patient had a Roux‐en‐Y gastric bypass and percutaneous endoscopic jejunostomy was performed. Technical success rate was 100% and no complications occurred. This case series shows that the EUS‐guided PEG technique is a safe alternative in patients deemed unfit for conventional PEG.
The gaze bias effect in toddlers: Preliminary evidence for the developmental study of visual decision‐making
Authors: Saito Toshiki , Sudo Ryunosuke , Takano Yuji
Published: April 2020

Several studies have investigated the interactive relationship between attention and decision‐making, which is known as the gaze bias effect. Although the generalizability of the gaze bias effect has recently been observed among young and older adults, it remains unknown in which developmental period individuals start to exhibit this relationship. This question was addressed in the current study by recruiting 58 toddlers aged 2–4 years. Participants were asked to do a two‐alternative forced‐choice task in which they chose one of two soft toys they preferred while their eye movements were recorded. Results demonstrated that toddlers exhibited gaze bias regardless of age. We also found that the number of gaze shifts during the task increased according to age. These results suggest that the interactive relationship between attention and decision is acquired by the age of two. The implications of the increased number of gaze shifts for visual decision‐making are discussed.
Treatment after inadequate immediate replantation of accidentally extracted immature mandibular premolar during primary molar extraction
Authors: Juloski Jelena , Dimitrijevic Maja , Juloski Jovana , Radovic Ivana
Published: April 2020

During extraction of the primary mandibular right second molar in an 11‐year‐old girl, the unerupted second premolar was accidentally extracted. Clinical and radiographic examination showed that the immediately replanted immature premolar was not oriented and positioned correctly. Four hours later, treatment consisted of manual extrusion of the permanent tooth bud, rotation, and gentle repositioning into its original position. Adequate replantation was confirmed by a post‐operative radiograph. After 2 years and 4 months, clinical examination revealed normal, healthy appearance of the replanted tooth, no sensitivity to percussion, no tenderness to palpation, and a slight response to a cold pulp sensibility test. A radiograph showed completely developed root with closed apical foramen, slightly irregular root morphology and shorter root length, complete obliteration of the pulp, and no signs of periapical pathosis.
Thioredoxin‐1 as a biological predictive marker for selecting diffuse large B‐cell lymphoma patients for etoposide‐containing treatment
Authors: Kari Esa Jarkko Mikael , Kuusisto Milla Elvi Linnea , Honkavaara Päivi , Hakalahti Anna , Haapasaari Kirsi‐Maria , Bloigu Risto , Karihtala Peeter , Teppo Hanna‐Riikka , Pirinen Risto , Turpeenniemi‐Hujanen Taina , Kuittinen Outi
Published: April 2020

Objective

In diffuse large B‐cell lymphoma (DLBCL), there is an unmet medical need to select patients who would benefit from intensified frontline treatments such as adding etoposide to an R‐CHOP regimen.

Methods

The present work included a retrospective clinical analysis of two patient cohorts and an in vitro study. Primary biopsy samples from DLBCL patients treated with an etoposide‐containing high‐dose regimen (n = 37) and etoposide‐containing frontline treatment (n = 69, R‐CHOEP) were studied using immunohistochemical thioredoxin‐1 (Trx1) staining. Two DLBCL cell lines expressing Trx1 were cultured, and their expression was silenced using the small interfering RNA knockdown technique. Chemoresistance was tested with doxorubicin, etoposide, vincristine, prednisolone and carboplatin.

Results

Thioredoxin‐1 knockdown sensitised DLBCL cells to doxorubicin (P < .0001) but decreased etoposide‐induced cell death (P < .00001). In DLBCL patients who received etoposide‐containing frontline treatment, low cytoplasmic Trx1 expression was associated with inferior 5‐year overall survival (46% vs 76%, P = .026) and disease‐specific survival (68% vs 90%, P = .026).

Conclusions

Strong Trx1 expression appears to increase drug resistance to doxorubicin but sensitises cells to etoposide. This implies that Trx1 expression might be the first predictive biological marker to select the patients who might benefit from adding etoposide to R‐CHOP immunochemotherapy.
Methodological approaches to understand the molecular mechanism of structural plasticity of dendritic spines
Authors: Mikuni Takayasu , Uchigashima Motokazu
Published: April 2020

Dendritic spines are tiny protrusions emanating from the neuronal dendrites, typically housing single excitatory postsynapses. Structural plasticity of dendritic spines is considered to be essential for synaptic functional plasticity and also reorganization of neural circuits during learning and memory. Structural plasticity of spines is mediated by complex biochemical signaling with various spatial and temporal scales. A variety of methods based on pharmacological, genetic, molecular, imaging and optical approaches has been developed and applied to dissect the complex signal transduction pathways. In this review, we overview both conventional and new methodological approaches to identify, monitor and manipulate key molecules for structural plasticity of dendritic spines, ultimately aiming to understand the molecular mechanism of learning and memory in behaving animals.
Differences in neurology residency training programmes across Europe – a survey among the Residents and Research Fellow Section of the European Academy of Neurology national representatives
Authors: Kleineberg N. N. , van der Meulen M. , Franke C. , Klingelhoefer L. , Sauerbier A. , Di Liberto G. , Carvalho V. , Berendse H. W. , Deuschl G.
Published: April 2020

Background and purpose

Neurology is rapidly evolving as a result of continuous diagnostic and therapeutic progress, which influences the daily work of neurologists. Therefore, updating residency training programmes is crucial for the future of neurology. Several countries are currently discussing and/or modifying the structure of their neurology residency training programme. A detailed and up‐to‐date overview of the available European residency training programmes will aid this process.

Methods

A questionnaire addressing numerous aspects of residency training programmes in neurology was distributed among 38 national representatives of the Resident and Research Fellow Section of the European Academy of Neurology.

Results

We obtained data from 32 European countries (response rate 84%). The median (range) duration of the residency training programmes was 60 (12–72) months. In the majority of countries, rotations to other medical disciplines were mandatory, mostly psychiatry (69%), internal medicine (66%) and neurosurgery (59%). However, the choice of medical fields and the duration of rotations varied substantially between countries. In 50% of countries, there were formal regulations regarding training in evidence‐based medicine, teaching skills and/or leadership qualities. In many countries (75%), residents had to take an examination.

Conclusions

We found substantial variation among European countries in the duration of residency training programmes, and especially in the choice of obligatory rotations to external medical disciplines. Despite a presumably similar spectrum of patients, neurology residency training programmes across Europe are not harmonized. The structure of the programme should be determined by its relevance for neurologists today and in the future.
Black holes and high levels of neurofilaments in glial fibrillary acidic protein – astrocytopathy: a case report
Authors: Papa A. , Tzartos J. S. , Sakoutis G. , Dardiotis E. , Alexiou E. , Breza M. , Velonakis G. , Papamichalis P. , Mpampalis D. , Komnos A. , Karagiorgou A. , Papakonstantinou A. , Kilidireas C. , Hadjigeorgiou G. M.
Published: April 2020

Background and purpose

Glial fibrillary acidic protein (GFAP) is an intracellular protein of the astrocytic cytoskeleton. Recently, autoantibodies to GFAP detected by cell‐based assay in cerebrospinal fluid (CSF) or serum have been implicated in cerebral astrocytopathy, presenting predominantly with autoimmune meningoencephalomyelitis. However, the phenotypic spectrum, prognosis and therapeutics of this new entity remain to be elucidated.

Methods

Herein, we report radiological, CSF and serological findings during disease exacerbation and remission, from a patient with autoimmune GFAP astrocytopathy, presenting as an immunotherapy responsive GFAP IgG‐associated meningoencephalomyelitis.

Results

Brain and spine magnetic resonance imaging revealed meningeal enhancement, T2 hyperintensities, black holes, significant sulci widening and spinal atrophy. In addition, high levels of neurofilaments (NfL) and GFAP were also identified during disease exacerbation, consistent with the appearance of the black holes.

Conclusions

To date, black holes and atrophy have never been reported before in autoimmune GFAP astrocytopathy. These findings, combined with the high levels of GFAP and NfL, suggest the existence of an underlying neurodegenerative mechanism in addition to the known inflammatory response. Further studies are needed to elucidate the pathomechanism of GFAP‐astrocytopathies.
Ectodermal dysplasia‐skin fragility syndrome: Two new cases and review of this desmosomal genodermatosis
Authors: Doolan Brent J. , Gomaa Nesrin S. , Fawzy Mohamed M. , Dogheim Noha N. , Liu Lu , Mellerio Jemima E. , Onoufriadis Alexandros , McGrath John A.
Published: April 2020

Background

Desmosomes are intercellular cadherin‐mediated adhesion complexes that anchor intermediate filaments to the cell membrane and are required for strong adhesion for tissues under mechanical stress. One specific component of desmosomes is plakophilin 1 (PKP1), which is mainly expressed in the spinous layer of the epidermis. Loss‐of‐function autosomal recessive mutations in PKP1 result in ectodermal dysplasia‐skin fragility (EDSF) syndrome, the initial inherited Mendelian disorder of desmosomes first reported in 1997.

Methods

To investigate two new cases of EDSF syndrome and to perform a literature review of pathogenic PKP1 mutations from 1997 to 2019.

Results

Sanger sequencing of PKP1 identified two new homozygous frameshift mutations: c.409_410insAC (p.Thr137Thrfs*61) and c.1213delA (p.Arg411Glufs*22). Comprehensive analyses were performed for the 18 cases with confirmed bi‐allelic PKP1 gene mutations, but not for one mosaic case or 6 additional cases that lacked gene mutation studies. All pathogenic germline mutations were loss‐of‐function (splice site, frameshift, nonsense) with mutations in the intron 1 consensus acceptor splice site (c.203‐1>A or G>T) representing recurrent findings. Skin fragility and nail involvement were present in all affected individuals (18/18), with most cases showing palmoplantar keratoderma (16/18), alopecia/hypotrichosis (16/18) and perioral fissuring/cheilitis (12/15; not commented on in 3 cases). Further observations in some individuals included pruritus, failure to thrive with low height/weight centiles, follicular hyperkeratosis, hypohidrosis, walking difficulties, dysplastic dentition and recurrent chest infections.

Conclusion

These data expand the molecular basis of EDSF syndrome and help define the spectrum of both the prototypic and variable manifestations of this desmosomal genodermatosis.