bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between attachment site of tibialis anterior muscle and shape of tibia: anatomical study of cadavers
Authors: Kimata Kentaro , Otsuka Shun , Yokota Hiroki , Shan Xiyao , Hatayama Naoyuki , Naito Munekazu
Published: July 2022

Background

Tibialis anterior (TA) muscle is the largest dorsiflexor of the ankle joint and plays an important role during gait movement. However, descriptions of the TA attachment site are inconsistent even among major anatomy textbooks, and its origin, especially the attachment site for the tibia, has not been reported in detail. This study is the first experimental attempt to investigate the origin of the TA in detail, paying particular attention to the relationship with the shape of the tibia, including sex differences.

Methods

Forty legs (20 males, 20 females) from twenty Japanese cadavers were examined. Gross anatomical examination of the TA's attachment site to the tibia and the tibia's shape was performed.

Results

The location of the distal end of the TA's attachment on tibia was significantly more distal in males than in females (p < 0.01). The anterior border of the tibia had a gentle S‐like curve, with a medially convex curve in the proximal region and a laterally convex curve in the distal region in frontal plane. The most protruding point of the distal curve of the anterior border located significantly more proximal in females than in males (p = 0.02).

Conclusions

There were sex differences in the distal end of the attachment site on tibia of the TA and the shape of the tibia. Consequently, the variations in the attachment site of TA were considered to provide for differences in function of TA. In males, the TA may enable advantageous power exertion, whereas in females it may work efficiently for dorsiflexion of ankle, respectively. Sex differences in TA's attachment site and the shape of the tibia may be involved in gait movement as well as frequency of lower leg disorders such as chronic exertional compartment syndrome.
Simulation-based randomized trial of medical emergency cognitive aids
Authors: Sellmann Timur , Alchab Samer , Wetzchewald Dietmar , Meyer Joerg , Rassaf Tienush , Thal Serge C. , Burisch Christian , Marsch Stephan , Breuckmann Frank
Published: July 2022

Background

Medical emergencies are complex and stressful, especially for the young and inexperienced. Cognitive aids (CA) have been shown to facilitate management of simulated medical emergencies by experienced teams. In this randomized trial we evaluated guideline adherence and treatment efficacy in simulated medical emergencies managed by residents with and without CA.

Methods

Physicians attending educational courses executed simulated medical emergencies. Teams were randomly assigned to manage emergencies with or without CA. Primary outcome was risk reduction of essential working steps. Secondary outcomes included prior experience in emergency medicine and CA, perceptions of usefulness, clinical relevance, acceptability, and accuracy in CA selection. Participants were grouped as “medical” (internal medicine and neurology) and “perioperative” (anesthesia and surgery) regarding their specialty. The study was designed as a prospective randomized single-blind study that was approved by the ethical committee of the University Duisburg-Essen (19-8966-BO). Trial registration: DRKS, DRKS00024781. Registered 16 March 2021—Retrospectively registered, http://www.drks.de/DRKS00024781.

Results

Eighty teams participated in 240 simulated medical emergencies. Cognitive aid usage led to 9% absolute and 15% relative risk reduction. Per protocol analysis showed 17% absolute and 28% relative risk reduction. Wrong CA were used in 4%. Cognitive aids were judged as helpful by 94% of the participants. Teams performed significantly better when emergency CA were available (p < 0.05 for successful completion of critical work steps). Stress reduction using CA was more likely in “medical” than in “perioperative” subspecialties (3.7 ± 1.2 vs. 2.9 ± 1.2, p < 0.05).

Conclusions

In a high-fidelity simulation study, CA usage was associated with significant reduction of incorrect working steps in medical emergencies management and was characterized by high acceptance. These findings suggest that CA for medical emergencies may have the potential to improve emergency care.
Towards defining morphologic parameters of normal parous and nulliparous breast tissues by artificial intelligence
Authors: Ogony Joshua , de Bel Thomas , Radisky Derek C. , Kachergus Jennifer , Thompson E. Aubrey , Degnim Amy C. , Ruddy Kathryn J. , Hilton Tracy , Stallings-Mann Melody , Vachon Celine , Hoskin Tanya L. , Heckman Michael G. , Vierkant Robert A. , White Launia J. , Moore Raymond M. , Carter Jodi , Jensen Matthew , Pacheco-Spann Laura , Henry Jill E. , Storniolo Anna Maria , Winham Stacey J. , van der Laak Jeroen , Sherman Mark E.
Published: July 2022

Background

Breast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described.

Methods

Using validated Artificial Intelligence and morphometric methods, we analyzed digitized images of tissue sections of normal breast tissues stained with hematoxylin and eosin from donors ≤ 45 years from the Komen Tissue Bank (180 parous and 545 nulliparous). Metrics assessed by AI, included: TDLU count; adipose tissue fraction; mean acini count/TDLU; mean dilated acini; mean average acini area; mean “capillary” area; mean epithelial area; mean ratio of epithelial area versus intralobular stroma; mean mononuclear cell count (surrogate of immune cells); mean fat area proximate to TDLUs and TDLU area. We compared epidemiologic characteristics collected via questionnaire by parity status and race, using a Wilcoxon rank sum test or Fisher’s exact test. Histologic features were compared between nulliparous and parous women (overall and by time between last birth and donation [recent birth: ≤ 5 years versus remote birth: > 5 years]) using multivariable regression models.

Results

Normal breast tissues of parous women contained significantly higher TDLU counts and acini counts, more frequent dilated acini, higher mononuclear cell counts in TDLUs and smaller acini area per TDLU than nulliparas (all multivariable analyses p < 0.001). Differences in TDLU counts and average acini size persisted for > 5 years postpartum, whereas increases in immune cells were most marked ≤ 5 years of a birth. Relationships were suggestively modified by several other factors, including demographic and reproductive characteristics, ethanol consumption and breastfeeding duration.

Conclusions

Our study identified sustained expansion of TDLU numbers and reduced average acini area among parous versus nulliparous women and notable increases in immune responses within five years following childbirth. Further, we show that quantitative characteristics of normal breast samples vary with demographic features and BC risk factors.
Network analysis of synovial RNA sequencing identifies gene-gene interactions predictive of response in rheumatoid arthritis
Authors: Sciacca Elisabetta , Surace Anna E. A. , Alaimo Salvatore , Pulvirenti Alfredo , Rivellese Felice , Goldmann Katriona , Ferro Alfredo , Latora Vito , Pitzalis Costantino , Lewis Myles J.
Published: July 2022

Background

To determine whether gene-gene interaction network analysis of RNA sequencing (RNA-Seq) of synovial biopsies in early rheumatoid arthritis (RA) can inform our understanding of RA pathogenesis and yield improved treatment response prediction models.

Methods

We utilized four well curated pathway repositories obtaining 10,537 experimentally evaluated gene-gene interactions. We extracted specific gene-gene interaction networks in synovial RNA-Seq to characterize histologically defined pathotypes in early RA and leverage these synovial specific gene-gene networks to predict response to methotrexate-based disease-modifying anti-rheumatic drug (DMARD) therapy in the Pathobiology of Early Arthritis Cohort (PEAC). Differential interactions identified within each network were statistically evaluated through robust linear regression models. Ability to predict response to DMARD treatment was evaluated by receiver operating characteristic (ROC) curve analysis.

Results

Analysis comparing different histological pathotypes showed a coherent molecular signature matching the histological changes and highlighting novel pathotype-specific gene interactions and mechanisms. Analysis of responders vs non-responders revealed higher expression of apoptosis regulating gene-gene interactions in patients with good response to conventional synthetic DMARD. Detailed analysis of interactions between pairs of network-linked genes identified the SOCS2/STAT2 ratio as predictive of treatment success, improving ROC area under curve (AUC) from 0.62 to 0.78. We identified a key role for angiogenesis, observing significant statistical interactions between NOS3 (eNOS) and both CAMK1 and eNOS activator AKT3 when comparing responders and non-responders. The ratio of CAMKD2/NOS3 enhanced a prediction model of response improving ROC AUC from 0.63 to 0.73.

Conclusions

We demonstrate a novel, powerful method which harnesses gene interaction networks for leveraging biologically relevant gene-gene interactions leading to improved models for predicting treatment response.
Level of health literacy in Latvia and Lithuania: a population-based study
Authors: Gatulytė Ieva , Verdiņa Valērija , Vārpiņa Zane , Lublóy Ágnes
Published: July 2022

Background

Measuring and understanding the level of health literacy serves as a starting point for developing various policies in health care. The consequences of weak health literacy competencies are severe; they result in riskier health behaviour, poorer health status, more frequent emergency visits and hospitalizations. This research has three aims: i) measure the level of health literacy in the populations of Latvia and Lithuania; ii) investigate which demographic and socioeconomic determinants are associated with it; and iii) discuss the means of improving its current level.

Methods

We employ a validated survey tool, the 47-item European Health Literacy Questionnaire (HLS-EU-Q). In addition to the 47 questions in the domains of health care, disease prevention, and health promotion, the participants’ demographic and socioeconomic characteristics are assessed. Face-to-face paper-assisted surveys are conducted with randomly selected residents from Latvia and Lithuania. The level of health literacy is measured by the health literacy index. Spearman correlation analyses and multiple regressions models are employed for investigating the association between the health literacy level and its determinants. The survey tool is complemented with in-depth interviews with six healthcare industry experts in order to assess the most promising ways to improve the level of health literacy.

Results

The stratified random sampling with quota elements assured a representative sample in terms of gender, urban/rural distribution and regions. In Latvia, 79% of the population possesses weak health literacy competencies. In Lithuania, 73% of the population can be characterized with inadequate or problematic level of health literacy. The most important determinants of the health literacy level include age, financial situation, social status, and ethnicity. In particular, elderly (aged 76 and over) and the Latvian-speaking population are less health literate, while those having better financial situation and higher social status are more health literate. The three most promising ways to improve the level of health literacy, as suggested by the healthcare industry experts, include health education in schools, provision of structured health-related information in Latvian and Lithuanian, and guidelines for the most common health problems.

Conclusions

The proportion of population with inadequate or problematic level of health literacy is higher in Latvia and Lithuania than in several other European countries. There is an urgent need to develop policies to improve it.
Crateva unilocularis Buch-Ham leaf extract improves glucose metabolism via regulation of insulin secretion and sensitivity in vitro and in vivo
Authors: Park Chul-Min , Jeong Bong-Hwa , Sharma Raj Bhesh , Kim Hyun-Jung , Kim Dong-Wook , Rhyu Dong-Young
Published: July 2022

Crateva unilocularisBuch-Ham has traditionally been used in Nepal for the treatment and prevention of diabetes. However, scientific verification through studies on the preventive effect ofC. unilocularison diabetes has not been done properly. In this study we investigated the effect ofC. unilocularisleaf extract (CULE) on glucose uptake and insulin resistance. The effect of CULE on glucose uptake in an in vivo system was measured using zebrafish. In the cell-free system, enzymes activities related to diabetes were measured. Moreover, in the cell-cultured system, RIN-m5F pancreatic beta cells, 3T3-L1 adipocytes, and L6 myotubes were used to measure the effect of CULE on insulin secretion and glucose metabolism. CULE effectively enhanced glucose uptake in zebrafish larvae, and inhibited the activity of dipeptidyl peptidase-IV (DPP-IV) and protein tyrosine phosphatase-1B (PTP-1B) enzymes related to insulin secretion and insulin signaling activation. Also, CULE significantly increased insulin secretion with suppression of NO production in RIN-m5F pancreatic beta cells. In L6 myotubes and TNF-α-induced insulin resistance model of 3T3-L1 adipocytes, CULE significantly increased glucose uptake and immunofluorescence staining of glucose transporter (GLUT)4 protein. Furthermore, the regulatory response of glucose metabolism by CULE was a close correlation with the activation of insulin signaling (IRβ, PI3K, AKT) and 5′-AMP-activated protein kinase (AMPK)α and the reduction of p38 mitogen-activated protein kinase (MAPK) in TNF-α-induced insulin resistance model of 3T3-L1 adipocytes. Thus, our results suggest that CULE may act as a potential agent for the prevention and treatment of metabolic syndrome associated with type 2 diabetes.
Practical significance of item misfit and its manifestations in constructs assessed in large-scale studies
Authors: Fährmann Katharina , Köhler Carmen , Hartig Johannes , Heine Jörg-Henrik
Published: July 2022

When scaling psychological tests with methods of item response theory it is necessary to investigate to what extent the responses correspond to the model predictions. In addition to the statistical evaluation of item misfit, the question arises as to its practical significance. Although item removal is undesirable for several reasons, its practical consequences are rarely investigated and focus mostly on main survey data with pre-selected items. In this paper, we identify criteria to evaluate practical significance and discuss them with respect to various types of assessments and their particular purposes. We then demonstrate the practical consequences of item misfit using two data examples from the German PISA 2018 field trial study: one with cognitive data and one with non-cognitive/metacognitive data. For the former, we scale the data under the GPCM with and without the inclusion of misfitting items, and investigate how this influences the trait distribution and the allocation to reading competency levels. For non-cognitive/metacognitive data, we explore the effect of excluding misfitting items on estimated gender differences. Our results indicate minor practical consequences for person allocation and no changes in the estimated gender-difference effects.
Presence of microplastics in drinking water from different freshwater sources in Flanders (Belgium), an urbanized region in Europe
Authors: Semmouri Ilias , Vercauteren Maaike , Van Acker Emmanuel , Pequeur Emmy , Asselman Jana , Janssen Colin
Published: July 2022

Microplastics (MPs) are emerging contaminants of concern in aquatic ecosystems. Up to now, only a few studies about MP contamination in drinking water have been published. In this study, we analysed drinking water originating from ground water, surface water and treated sewage water for the presence of MPs, collected in different drinking water treatment plants (DWTP, n = 9) and water taps (TW, n = 9) in the geographic region of Flanders (Belgium). We report measured microplastic concentrations, size distributions, and polymer types using μFTIR spectroscopy in the range of 25–1000 μm. The MPs’ abundances in the DWTP and TW samples were on average 0.02 ± 0.03 MPs L− 1 and 0.01 ± 0.02 MPs L− 1, respectively. We did not find significant differences comparing the obtained MP concentrations according to the origin of the water. Polypropylene (PP) and polyethylene terephthalate (PET) were the most common polymer types detected in the samples. Next, based on several theoretical assumptions, we extrapolated the measured MP concentrations in our samples to cover the full theoretical MP size range (1–5000 μm) to obtain estimates of the actual MP contamination levels. The rescaled particle concentrations (1 μm – 5000 mm) were on average 5.59 MPs L− 1 and 3.76 MPs L− 1 for the DWTP and TW samples, respectively. Based on a standard consumption of two liters of drinking water per day in combination with the measured concentration in this study, Flemish people consume 0.02 MPs per capita per day via drinking water. These findings contribute in our understanding of the microplastic pollution of drinking water, which is of concern due to the potential uptake of MPs in the human body.
Performance assessment of radio occultation data from GeoOptics by comparing with COSMIC data
Authors: Chang Hyeyeon , Lee Jiyun , Yoon Hyosang , Morton Y. Jade , Saltman Alex
Published: July 2022

Responding to the ever-growing demand for environmental information, the National Oceanic and Atmospheric Administration (NOAA) seeks to enter into contracts to purchase Global Navigation Satellite System (GNSS) radio occultation (RO) observations produced by commercial vendors at a low-cost. GeoOptics is one commercial vendor awarded a contract with NOAA. GeoOptics operates the Community Initiative for Cellular Earth Remote Observation (CICERO) constellation of low-earth-orbiting (LEO) 6U CubeSats. The 6U-sized CICERO will enable the deployment of GNSS array consisting of RO satellites in the Earth’s atmosphere to obtain many atmospheric observations which can improve weather forecasting. Applying GeoOptics RO data to reliable weather forecasting requires an assessment of its performance. This study analyzes the performance of GeoOptics CubeSats measurements by comparing it with the Constellation Observing System for Meteorology, Ionosphere, and Climate (COSMIC) missions (COSMIC-1 and COSMIC-2). The performance analysis was carried on data coverage capabilities and measurement quality. The analysis of data coverage confirmed that GeoOptics can acquire global observational coverage with adequate low-altitude penetration capability, while there should be updated in local time coverage. The analysis of RO measurement quality showed that GeoOptics RO measurements are comparable to those of COSMIC-2, even though GeoOptics exhibited a lower signal-to-noise ratio (SNR). The potential of GeoOptics allows for the development of a GNSS array in the Earth’s atmosphere and a large amount of effective RO measurements to be obtained for reliable weather forecasting.

Graphical Abstract
Changing mortality amongst hospitalised children with Severe Acute Malnutrition in KwaZulu-Natal, South Africa, 2009 – 2018
Authors: Ndlovu S , David-Govender C , Tinarwo P , Naidoo KL
Published: July 2022

Background

The under-five mortality rates of children in South Africa (SA) remain high despite successful HIV prevention and treatment programs. The in-hospital mortality of children with severe acute malnutrition remains a key obstacle. This study identifies and describes changes in the mortality of under-five children with severe acute malnutrition (SAM) following the implementation of HIV and malnutrition prevention and treatment programmes.

Methods

This was a retrospective review of in-hospital mortality records and databases. The study was based at a large referral hospital in KwaZulu-Natal (KZN), where HIV and malnutrition rates are high, and SAM children are managed with standard WHO guidelines. Records of children under five years old who died from 2009 to 2018 were analysed.

Results

Of the 698 under-five children who died in this period, 285 (40, 8% of all under-5 deaths) were classified as having SAM. The number of HIV-infected SAM deaths dropped significantly, especially those below six months of age, mirroring the expansion of HIV treatment and prevention programmes. Despite this and a significant drop in the proportion of SAM admissions identified, there was no change in SAM case fatality rates over the ten years. Septicaemia remained the most common cause of death in children with SAM.

Conclusions

Despite significant decreases in HIV-related malnutrition deaths over ten years, the lack of change in SAM case fatality rates is a concern at this referral hospital. Standardised WHO inpatient management protocols, may require review, especially where underlying medical conditions may contribute to SAM deaths in HIV-negative children.
Investigating the feasibility and effectiveness of a modular treatment program for children and adolescents with depression and interpersonal problems: study protocol of a quasi-experimental pilot feasibility trial (CBASP@YoungAge)
Authors: Dippel N. , In-Albon T. , Schneider S. , Christiansen H. , Brakemeier E.-L.
Published: July 2022

Background

Depression is a serious disorder in childhood and adolescence. Affected children and adolescents show significant impairments in various aspects of life. Studies on the effectiveness or efficacy of psychotherapy in depressed children and adolescents are qualitatively very heterogeneous and reveal small effect sizes. There is thus a need to better tailor psychotherapy approaches to these age groups to improve outcomes like parent-child relationship, symptomatology, or quality of life.

To address this gap, we designed a modular, individualized treatment program for children and adolescents based on the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) including caregiver involvement.

Method

This quasi-experimental pilot feasibility trial is a phase 1 to phase 2 study investigating the feasibility and effectiveness of CBASP@YoungAge by including an intervention group (CBASP@YoungAge) and a treatment-as-usual control group. The treatment of depressive symptoms as well as interpersonal problems with primary caregivers are the main targets of CBASP@YoungAge. Personalization is ensured concerning the treatment course, caregivers’ involvement, and the patient’s age. The primary outcome relates to two areas: the feasibility of the CBASP@YoungAge treatment program in an outpatient context and a change in patients' depressive symptomatology from before to after treatment. We conduct a brief process evaluation after each session in the intervention group to closely monitor the treatment process and examine feasibility from the therapists' and patients' perspectives and mechanisms of symptom change. In addition, we consider interpersonal behavior between children and caregivers, parenting behavior, and monitor the global-health-index in children and parents as secondary outcomes. Pre-, post-, and follow-up data are evaluated.

Discussion

This is the first study of a modular-based intervention program for children and adolescents with depression and a clear focus on the interpersonal problems between the depressed young patient and her/his caregiver. It will provide important knowledge on the feasibility and effectiveness of the program and potential benefits of including caregivers in psychotherapy. Based on this study’s results, we plan a multicenter, randomized, controlled trial whose long-term aim is to improve the psychotherapeutic care of young patients with depression while preventing persistent courses of depressive disorders.

Trial registration

German Clinical Trials Register, DRKS (identifierDRKS00023281). Registered 17 November 2020–Retrospectively registered
COVID-19 as a putative trigger of anti-MDA5-associated dermatomyositis with acute respiratory distress syndrome (ARDS) requiring lung transplantation, a case report
Authors: Anderle Karolina , Machold Klaus , Kiener Hans P. , Bormann Daniel , Hoetzenecker Konrad , Geleff Silvana , Prosch Helmut , Laccone Franco , Heil Peter M. , Petzelbauer Peter , Aletaha Daniel , Blüml Stephan , Kastrati Kastriot
Published: July 2022

Background

Autoimmune disease following COVID-19 has been studied intensely since the beginning of the pandemic. Growing evidence indicates that SARS-CoV-2 infection, by virtue of molecular mimicry can lead to an antigen-mediated cross-reaction promoting the development of a plethora of autoimmune spectrum diseases involving lungs and extrapulmonary tissues alike. In both COVID-19 and autoimmune disease, the immune self-tolerance breaks, leading to an overreaction of the immune system with production of a variety of autoantibodies, sharing similarities in clinical manifestation, laboratory, imaging, and pathology findings. Anti-Melanoma Differentiation-Associated gene 5 dermatomyositis (anti-MDA5 DM) comprises a rare subtype of systemic inflammatory myopathies associated with characteristic cutaneous features and life-threatening rapidly progressive interstitial lung disease (RP-ILD). The production of anti-MDA5 autoantibodies was proposed to be triggered by viral infections.

Case presentation

A 20-year-old male patient with polyarthritis, fatigue and exertional dyspnea was referred to our department. An elevated anti-MDA5 autoantibody titer, myositis on MRI, ground glass opacifications on lung CT and histological features of Wong-type dermatomyositis were confirmed, suggesting the diagnosis of an anti-MDA5 DM. Amid further diagnostic procedures, a serologic proof of a recent SARS-CoV-2 infection emerged. Subsequently, the patient deteriorated into a fulminant respiratory failure and an urgent lung transplantation was performed, leading to remission ever since (i.e. 12 months as of now).

Conclusions

We report a unique case of a patient with a new-onset anti-MDA5 DM with fulminant ARDS emerging in a post-infectious stage of COVID-19, who underwent a successful lung transplantation and achieved remission. Given the high mortality of anti-MDA5 DM associated RP-ILD, we would like to highlight that the timely recognition of this condition and urgent therapy initiation are of utmost importance.
Nephroblastoma Treatment and Outcomes in a Low-Income Setting
Authors: Shyirambere Cyprien , Villaverde Chandler , Nguyen Cam , Ruhangaza Deogratias , Umwizerwa Aline , Nsanzimana Oscar , Mujyuwisha Louis , Iradukunda Esperance , Shulman Lawrence N. , Lehmann Leslie
Published: July 2022

PURPOSE

Nephroblastoma is a highly curable pediatric cancer that requires multidisciplinary care. Few reports have assessed long-term treatment outcomes in low-resource settings using a task-shifting model of care. We report outcomes of a large cohort and factors associated with survival.

METHODS

We performed a retrospective chart review of all patients with nephroblastoma presenting to the Butaro Cancer Center of Excellence in Rwanda between July 2012 and June 2018.

RESULTS

In total, 136 patients were identified and treated according to International Society of Pediatric Oncology guidelines for low-income settings. Median age at diagnosis was 39.7 months (interquartile range, 25.3-61.8 months); 56.6% were female. Sixty-one (44.9%) patients presented with stage I-III disease, 35 (25.7%) with stage IV disease, and 6 (4.4%) with stage V disease; the remainder were unstaged (n = 34; 25.0%). Most patients completed surgery (n = 97; 71.3%) and postoperative chemotherapy (n = 82; 60.2%); 17 patients received radiotherapy. With a median follow-up time of 18.1 months, 44.9% of patients were alive, 41.9% had died, 8.8% were lost to follow-up, and 4.4% were referred for palliative care or declined further care at the end of the study. Three-year overall survival was 57.5% (95% CI, 48.1 to 65.8) for the entire cohort, and 80.1% (95% CI, 66.8 to 88.5) and 44.0% (95% CI, 26.8 to 60.0) for stages I-III and IV-V, respectively.

CONCLUSION

We demonstrate that patients with nephroblastoma can be successfully treated in a low-resource setting. Survival remains lower than in high-income countries, in part due to early deaths, contributing to approximately 30% of patients not being medically able to receive surgical intervention. Next steps include the development of strategies that focus on earlier diagnosis, supportive care during the early phases of therapy, and efficient and timely transitions between specialties for multimodal care.
Comparison of Titer and Signal to Noise (S/N) for Determination of Anti-drug Antibody Magnitude Using Clinical Data from an Industry Consortium
Authors: Starcevic Manning Marta , Hassanein Mohamed , Partridge Michael A. , Jawa Vibha , Mora Johanna , Ryman Josiah , Barker Breann , Braithwaite Christian , Carleton Kevin , Hay Laura , Hottenstein Charles , Kubiak Robert J. , Devanarayan Viswanath
Published: July 2022

During biotherapeutic drug development, immunogenicity is evaluated by measuring anti-drug antibodies (ADAs). The presence and magnitude of ADA responses is assessed using a multi-tier workflow where samples are screened, confirmed, and titered. Recent reports suggest that the assay signal to noise ratio (S/N) obtained during the screening tier correlates well with titer. To determine whether S/N could more broadly replace titer, anonymized ADA data from a consortium of sponsors was collected and analyzed. Datasets from clinical programs with therapeutics of varying immunogenicity risk levels (low to high), common ADA assay platforms (ELISA and MSD) and formats (bridging, direct, solid-phase extraction with acid dissociation), and titration approaches (endpoint and interpolated) were included in the analysis. A statistically significant correlation between S/N and titer was observed in all datasets, with a strong correlation (Spearman’s r > 0.8) in 11 out of 15 assays (73%). For assays with available data, conclusions regarding ADA impact on pharmacokinetics and pharmacodynamics were similar using S/N or titer. Subject ADA kinetic profiles were also comparable using the two measurements. Determination of antibody boosting in patients with pre-existing responses could be accomplished using similar approaches for titer and S/N. Investigation of factors that impacted the accuracy of ADA magnitude measurements revealed advantages and disadvantages to both approaches. In general, S/N had superior precision and ability to detect potentially low affinity/avidity responses compared to titer. This analysis indicates that S/N could serve as an equivalent and in some cases preferable alternative to titer for assessing ADA magnitude and evaluation of impact on clinical responses.

Graphical Abstract
PILS proteins provide a homeostatic feedback on auxin signaling output
Authors: Feraru Elena , Feraru Mugurel I. , Moulinier-Anzola Jeanette , Schwihla Maximilian , Ferreira Da Silva Santos Jonathan , Sun Lin , Waidmann Sascha , Korbei Barbara , Kleine-Vehn Jürgen
Published: July 2022

Multiple internal and external signals modulate the metabolism, intercellular transport and signaling of the phytohormone auxin. Considering this complexity, it remains largely unknown how plant cells monitor and ensure the homeostasis of auxin responses. PIN-LIKES (PILS) intracellular auxin transport facilitators at the endoplasmic reticulum are suitable candidates to buffer cellular auxin responses because they limit nuclear abundance and signaling of auxin. We used forward genetics to identify gloomy and shiny pils (gasp) mutants that define the PILS6 protein abundance in a post-translational manner. Here, we show that GASP1 encodes an uncharacterized RING/U-box superfamily protein that impacts on auxin signaling output. The low auxin signaling in gasp1 mutants correlates with reduced abundance of PILS5 and PILS6 proteins. Mechanistically, we show that high and low auxin conditions increase and reduce PILS6 protein levels, respectively. Accordingly, non-optimum auxin concentrations are buffered by alterations in PILS6 abundance, consequently leading to homeostatic auxin output regulation. We envision that this feedback mechanism provides robustness to auxin-dependent plant development.
Drying-Induced Surface Wrinkles Generated on Chitosan Films Having Polyion Complex Skin Layers: Effects of Physical Properties of Skin Layers and Substrates on Surface Wrinkling upon Drying
Authors: Izawa Hironori , Ishisaka Shota , Saimoto Hiroyuki , Ifuku Shinsuke
Published: July 2022

The effects of the physical properties of skin layers and substrates on drying-induced surface wrinkling are investigated with a system using chitosan films having polyion complex (PIC) skin layers. The PIC layers are fabricated with diverse anionic polymers having similar molecular weights on a chitosan (CS) film surface, and the films are dried. In all cases, surface wrinkles form but their sizes vary widely depending on the molecular structure. In particular, wrinkles formed with ligninsulfonate are much larger than those formed with the others. The skin layers differ significantly in surface hardness but not in thickness, indicating that wrinkle sizes induced by PIC skin layers are predominately determined by the hardness of the layers or by physical properties affected by hardness, such as shrinkage volume. The effects of the elastic moduli and shrinkage volume of the substrates are evaluated with higher molecular weight CS and surface-deacetylated chitin nanofiber composite CS films that have different elastic moduli but show very similar swelling–drying behaviors. The wrinkle sizes and skin layer thicknesses also suggest that wrinkle size in this system depends on the hardness of the skin layers or on the physical properties affecting the hardness.
Substrate-Specific Activation and Long-Range Olefin Migration Catalysis at the Pd Centers in a Porous Metal-Macrocycle Framework
Authors: Han Mengying , Tashiro Shohei , Shiraogawa Takafumi , Ehara Masahiro , Shionoya Mitsuhiko
Published: July 2022

Developing catalysts comparable to natural enzymes that achieve only specific reactions has long been a key challenge in the field of molecular synthesis. Long-range olefin migration reactions have attracted great interest as molecular transformation reactions that can realize remote re-functionalization of a molecule with high atom economy. Herein we report that linear alkenyl alcohols of a certain chain length can chemically activate Pd centers precisely arranged in a porous metal-macrocycle framework (MMF), thereby promoting substrate-specific, catalytic long-range olefin migration reactions that produce aldehydes or ketones. Furthermore, MMF can be chemically activated by highly reactive alkenyl alcohol substrates, converting another olefinic substrate that normally would not react with nonactivated MMF into an olefin-migrated product at a high conversion. These reaction specificities are discussed in relation to the arrangement mode of the Pd active centers in the confined space.
Does pre-operative breast MRI have an impact on surgical outcomes in high-grade DCIS?
Authors: Healy Nuala A. , Parag Yethiksha , Soppelsa Giorgia , Wignarajah Primee , Benson John R. , Agrawal Amit , Forouhi Parto , Kilburn-Toppin Fleur , Gilbert Fiona J.
Published: July 2022

Objectives:

High-grade DCIS (HG DCIS) is associated with upgrade to invasive disease but few studies evaluate the role of MRI in this subset of DCIS. This study compared surgical outcomes of females with HG DCIS on biopsy who had pre-operative MRI with those that proceeded directly to surgery.

Methods:

This single-centre retrospective, observational study identified patients with pure HG DCIS on pre-operative biopsy from the pathology database. Surgical outcomes, clinicopathological and radiological features were obtained for all patients.

Results:

From August 2015 to February 2020, 217 patients had HG DCIS on biopsy. Pre-operative MRI was performed in 40 (MRI group) and not in 88 (No MRI group) patients. Initial mastectomy was performed in 25/40 (63%) women in the MRI group and 20/88 (23%) women in the no MRI group (p < 0.0001). No difference was observed in re-operation rate between the two groups, 15% in MRI group vs 22% in No MRI group (p = 0.4749). Mean tumour size on histology was larger in mastectomy cases in the MRI group (73.4 mm, range 6–140 mm), than the total MRI group, (58.3 mm, range 0–140 mm) or no MRI group (30.7 mm, range 0–130 mm) (p < 0.0001).

Conclusions:

Pre-operative MRI in HG DCIS is associated with higher mastectomy rates, possibly due to patient selection for MRI, as tumours on final histology were significantly larger. Fewer re-operations were observed in the MRI group although this was not significant.

Advances in knowledge:

Breast MRI performed pre-operatively in HG DCIS is associated with higher mastectomy rates and fewer re-operation rates.
Breast calcification micromorphology classification
Authors: Scott Robert , Lyburn Iain , Cornford Eleanor , Bouzy Pascaline , Stone Nicholas , Greenwood Charlene , Bouybayoune Ihsanne , Pinder Sarah , Rogers Keith
Published: July 2022

Objectives:

The importance of consistent terminology in describing the appearance of breast calcifications in mammography is well recognised. Imaging of calcifications using electron microscopy is a globally growing field of research. We therefore suggest that the time is ripe to develop a lexicon of terms for classifying the micromorphology of breast calcifications.

Methods:

Calcifications within a wide range of histological sections of breast tissue, both benign and malignant, were imaged by Scanning Electron Microscopy (SEM). These images were examined, and the micromorphology of calcifications present was grouped to create a classification system.

Results:

Based on the appearance of the calcifications observed, we propose five main categories for classification of the micromorphology of breast calcifications, namely, Dense Homogenous, Punctulate, Banded, Spongy and Aggregate.

Conclusions:

Use of the descriptive categories outlined here will help to ensure consistency and comparability of published observations on the micromorphology of breast calcifications.

Advances in knowledge:

This is the first time a lexicon and classification system has been proposed for the micromorphology of breast calcifications, as observed by scanning electron microscopy of histological sections. This will facilitate comparability of observed relationships between micromorphology, mammographic appearance, chemistry and pathology.
Το νομοθετικό και θεσμικό πλαίσιο της εκπαίδευσης των επαγγελματιών μουσικών εκτελεστών στην Ελλάδα, από το 1871 μέχρι σήμερα
Authors: Αντανασιώτης-Αναργύρου Γεώργιος
Published: July 2022

Η διατριβή στοχεύει στην ανίχνευση, συγκέντρωση και αξιολόγηση της νομοθεσίας, η οποία διέπει την εκπαίδευση των επαγγελματιών μουσικών εκτελεστών στην Ελλάδα, λόγω της έλλειψης κωδικοποίησης μέχρι σήμερα. Το σύνολο των νόμων για πρώτη φορά οργανώνεται ως μία νομική εργαλειοθήκη, θεματικά και χρονικά. Όσες διατάξεις έχουν συμπεριληφθεί συνδέονται με εκπαιδευτικές διαδικασίες οι οποίες αποσκοπούν στην εκμάθηση των μουσικών οργάνων, της φωνητικής τέχνης και της διεύθυνσης μουσικών συνόλων, με τελικό σκοπό τη διάπλαση μιας άρτιας μουσικής προσωπικότητας, ικανής να δραστηριοποιηθεί επαγγελματικά ως μέλος σε ορχήστρες, σε μουσικά σύνολα, ή ως σολίστ. Η διατριβή στον πυρήνα της διερευνά το νομοθετικό και θεσμικό πλαίσιο των ποικίλλων μουσικών εκπαιδευτικών φορέων, από της ιδρύσεως του ελληνικού κράτους (1833) μέχρι σήμερα, συμπεριλαμβανομένων και αυτών του ευρύτερου ελληνικού χώρου (Ιόνιος Πολιτεία). Από το σύνολο των φορέων αυτών, διακρίνονται το Ωδείο Αθηνών (1871), το Κρατικό Ωδείο Θεσσαλονίκης (1914) και τα Τμήματα Μουσικών Σπουδών των ΑΕΙ (1984). Ως κυρίαρχα ζητήματα αναδεικνύονται η έλλειψη διαβάθμισης των απονεμόμενων τίτλων σπουδών των Ωδείων και των Μουσικών Σχολών, η απουσία επαγγελματικού ή ακαδημαϊκού αντικρίσματος, η πλήρης απαξίωση των πολυετών σπουδών και η ασυμβατότητα με το νομοθετικό πλαίσιο των ευρωπαϊκών κρατών. Αντιθέτως, η φοίτηση που πραγματοποιείται στα ακαδημαϊκά μουσικά τμήματα είναι εναρμονισμένη με τα ευρωπαϊκά πρότυπα (Bologna Process) και οδηγεί στη λήψη τίτλων σπουδών με αντιστοιχία στο 6ο , 7ο και 8ο επίπεδο του Ευρωπαϊκού Πλαισίου Επαγγελματικών Προσόντων (European Qualifications Framework).Στο τελευταίο μέρος της διατριβής διατυπώνονται τα συμπεράσματα, επιδιώκοντας τη συνεισφορά στην έρευνα και στην έναρξη ενός επιστημονικού διαλόγου αναφορικά με τη διαμόρφωση ενός ολοκληρωμένου και σύγχρονου νομοθετικού πλαισίου, ικανού να καλύψει επαρκώς τις εκπαιδευτικές ανάγκες των σπουδαστών, προστατεύοντας ταυτόχρονα τα επαγγελματικά τους δικαιώματα ως μουσικών εκτελεστών.
Investigative analysis of the combined cellular expression of survivin and PTEN, in ophthalmic pterygium, with the application of liquid face cytology
Authors: Κωνσταντοπούλου Καλλιρρόη
Published: July 2022

Σκοπός: Στη παθογένεια του πτερυγίου, τα υψηλά επίπεδα έκθεσης στην υπεριώδη ακτινοβολία, φαίνεται να έχουν τον πρωτεύοντα ρόλο, για την εμφάνιση του. Η σημασία όμως, της απορρύθμισης συγκεκριμένων γονίδιων, όπως είναι οι αποπτωτικοί και αντιαποπτωτικοί παράγοντες και κατασταλτικά της ογκογένεσης γονίδια, στη διαταραχή των μεταγωγικών σημάτων στο εσωτερικό του κυττάρου, δεν έχει διασαφηνιστεί. Στη παρούσα μελέτη, συν αναλύουμε τα πρωτεϊνικά προϊόντα των γονίδιων Survivin, p53 και PTEN, σε οφθαλμικά πτερύγια συγκριτικά με το επιθήλιο του υγιή επιπεφυκότα.Μέθοδος: Με κυτταρολογία υγρής φάσης, αναλυθήκαν πενήντα (50) κυτταρικά δείγματα, που λήφθηκαν με ήπια απόξεση του επιθήλιου του επιπεφυκότα. Από αυτά τα δείγματα, τριάντα οκτώ (38) προέρχονταν από παθολογικό ιστό, από την περιοχή του πτερυγίου και τα υπόλοιπα δώδεκα (12) δείγματα, ήταν από φυσιολογικό επιπεφυκότα. Έγινε ανοσοκυτταροχημική μελέτη των αντίστοιχων πλακιδίων με εφαρμογή αντι- p53, -Survivin και -PTEN αντισωμάτων και ψηφιακή ανάλυση της εικόνας για την ακριβή εκτίμηση της έντασης της ανοσοχημικής χρώσης.Αποτελέσματα: H πλειοψηφία των εξετασθέντων ιστών, από πτερύγια, εμφάνισαν υπερέκφραση των πρωτεϊνών (p53: 22/38 – 57.9%, survivin: 30/38 – 78.9%, PTEN: 25/38 – 65.7%, αντίστοιχα). Ενδιαφέρον έχει, η στατιστική σημασία που εντοπίσαμε στη συνδυασμένη υπερέκφραση των p53 και PTEN, με τιμή σημαντικότητας (p = 0.022). Η υπερέκφραση της Survivin και η υπερέκφραση της p53, σχετιζόταν με τα παθολογικά επιθήλια, με τιμή σημαντικότητας (p = 0.019 και p = 0.03, αντίστοιχα). Δεν διαπιστώθηκε, στατιστικά σημαντική σχέση ανάμεσα στην έκφραση των συγκεκριμένων πρωτεϊνών και την ανατομική θέση (επεκτεινόμενο κεντρικά/περιοριζόμενο στο ΣΚΟ), η μορφολογία (συμπαγές/ατροφικό) των πτερυγίων.Συμπεράσματα: Η υπερεκφραση της survivin, οδηγεί το κύτταρο σε αυξημένη αντιαποπτωτική δραστηριότητα και αποδεικνύει το σημαντικό ρόλο της στην εμφάνιση και εξέλιξη του πτερυγίου. Επιπρόσθετα, η σε μικρότερο βαθμό έκφραση του p53 , ενισχύει την άποψη ότι η επίδραση του είναι αμφιλεγόμενη, σε σύγκριση με την survivin. Η σημασία του PTEN, από τη μελέτη μας, αναδεικνύεται σημαντική, καθώς φαίνεται να επιτελεί ένα κατασταλτικό - ρυθμιστικό ρόλο στην ισορροπία του συμπλέγματος survivin / p53, πάρα την έλλειψη άλλων μελετών.
Η μελέτη των κεραμικών τεχνολογικών παραδόσεων στο ΥΜΙ κτηριακό συγκρότημα του Βαθυπέτρου Αρχανών ως μέσο διερεύνησης της κοινωνίας και της οικονομίας της νεοανακτορικής βορειοκεντρικής Κρήτης
Authors: Σταματάκη Παρασκευή
Published: July 2022

Το ΥΜΙ κτηριακό συγκρότημα του Βαθυπέτρου Αρχανών στην περιοχή του όρους Γιούχτα είναι ένα από τα σημαντικότερα περιφερειακά κέντρα που χτίστηκαν κατά τη Νεοανακτορική περίοδο στην Κρήτη, στα οποία γίνεται αναφορά με τους συμβατικούς όρους «βίλα», «μέγαρο», «έπαυλη» ή «αγροικία». Η παρούσα διατριβή εξετάζει τη λειτουργία και τον ρόλο του σημαντικού αυτού συγκροτήματος, τη χρονολόγηση των λειτουργικών του φάσεων, όπως και πτυχές της οργάνωσής του, στο πλαίσιο των κοινωνικο-οικονομικών συνθηκών της νεοανακτορικής βορειοκεντρικής Κρήτης. Για την πραγματοποίηση του προαναφερθέντος στόχου εδραιώθηκε μία λεπτομερής κεραμική τεχνολογική τυπολογία, με τη συστηματική διερεύνηση, μέσω μακροσκοπικής και πετρογραφικής εξέτασης, και καταγραφή των κυριότερων τεχνολογικών χαρακτηριστικών επιλεγμένων αγγείων μικρού και μέσου μεγέθους (κυρίως προχυτικών αγγείων και κυπέλλων) με προέλευση τα στρώματα της τελικής χρήσης της Βόρειας και της Νότιας Πτέρυγας του συγκροτήματος. Με βάση την προτεινόμενη μεθοδολογική προσέγγιση, τεκμηριώθηκαν οι κύριες κεραμικές τεχνολογικές παραδόσεις στο συγκρότημα, οι οποίες χρονολογήθηκαν στο τέλος της ΥΜΙβ περιόδου, ενώ, παράλληλα, υποδείχθηκε η ύπαρξη κεραμικών εργαστηρίων της ίδιας περιόδου, μόνιμων ή προσωρινών (δηλαδή μετακινούμενων), στην περιοχή του Γιούχτα, τα οποία παρήγαν μη μαγειρική κεραμική διαφόρων μεγεθών. Τα παραπάνω στοιχεία, σε συνδυασμό με την εξέταση της χρήσης και της σημασίας των αγγείων, έδειξαν ότι το Βαθύπετρο, στην αρχική και κύρια λειτουργική φάση του, στο τέλος της ΥΜΙβ περιόδου, εκτός από βιοτεχνικό - εργαστηριακό, αποθηκευτικό, διοικητικό και οικιστικό κέντρο, υπήρξε ένα κέντρο συνάντησης ή συναλλαγών, το οποίο οργάνωνε - ή επέτρεπε να οργανώνονται - στον χώρο του ειδικές κοινωνικές περιστάσεις και συναθροίσεις που περιλάμβαναν συμποσιακά τελετουργικά δρώμενα κοσμικού χαρακτήρα με σημαντικό αριθμό συμμετεχόντων. Η διοίκηση του Βαθυπέτρου είχε την οικονομική δυνατότητα διαχείρισης των αγαθών που καταναλώνονταν στα εν λόγω συμπόσια, προϊόντα τα οποία, δεν αποκλείεται, επιπλέον, να προσφέρονταν ως βοήθεια σε ενοίκους και περιοίκους τη δύσκολη αυτή περίοδο των φυσικών καταστροφών. Το παραπάνω στοιχείο, σε συνδυασμό με το γεγονός ότι σε όλες τις προϊστορικές κοινωνίες η οικονομική εξουσία είχε αναπόσπαστα, εκτός από θρησκευτικό, και πολιτικό ρόλο, θα απέδιδε θρησκευτική και πολιτικο-οικονομική ισχύ στη διοίκηση του Βαθυπέτρου ή σε αυτούς που έλεγχαν το κτηριακό συγκρότημα. Τα δεδομένα δείχνουν, πως μετά την πιθανή καταστροφή από σεισμό ή σεισμούς στο τέλος της αρχικής φάσης, λίγο πριν το τέλος της ΥΜΙβ περιόδου, το συγκρότημα επαναλειτούργησε για σύντομο χρονικό διάστημα σε συνθήκες έκτακτης ανάγκης, που περιλάμβαναν τη βασική προετοιμασία φαγητού και, ενδεχομένως, τελετουργικές δραστηριότητες, οι οποίες, όμως, δεν χαρακτηρίζονταν από την αίγλη και τον κοσμικό χαρακτήρα των προγενέστερων τελετουργικών συμποσίων.