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Abstract The freezing of water is one of the major causes of mechanical damage in materials during wintertime; surprisingly this happens even in situations where water only partially saturates the material so that the ice has room to grow. Here we perform freezing experiments in cylindrical glass vials of various sizes and wettability properties, using a dye that exclusively colors the liquid phase; this allows precise observation of the freezing front. The visualization reveals that damage occurs in partially water-saturated media when a closed liquid inclusion forms within the ice due to the freezing of the air/water meniscus. When this water inclusion subsequently freezes, the volume expansion leads to very high pressures leading to the fracture of both the surrounding ice and the glass vial. The pressure can be understood quantitatively based on thermodynamics which correctly predicts that the crystallization pressure on the inclusion boundary is independent of the volume of the liquid pocket. Finally, our results also reveal that by changing the wetting properties of the confining walls, the formation of the liquid pockets that cause the mechanical damage can be avoided.

A 13-year-old girl with Jervell and Lange-Nielsen syndrome associated congenital long QT syndrome (LQTS) and central deafness was admitted for generalized seizures. LQTS had been diagnosed after birth and confirmed at genetic testing. β-blocker treatment was immediately started. Despite this, since the age of 12 months, recurrent cerebral seizures occurred leading to the diagnosis of epilepsy. Anti-convulsive therapy was initiated but without success. At the last admission, nadolol dosage seemed infratherapeutic. Considering malignant ventricular arrhythmias as the cause of seizures, the β-blocker dosage was adjusted to weight and levels of magnesium and potassium optimized. Furthermore, the patient received an implantable Medtronic Reveal LINQ Recorder®. Since then, the adolescent has been asymptomatic with no arrhythmia documented. LQTS is due to one or more mutations of genes coding for ion channels. It may induce malignant ventricular arrhythmias and is a major cause of sudden cardiac death in children. Generalized cerebral seizures are extra-cardiac manifestations caused by decreased cerebral perfusion during ventricular arrhythmia. They are commonly misinterpreted as manifestations of epilepsy. For any patient with known or unknown LQTS who presents seizures with resistance to anti-convulsive therapy, a cardiac electrophysiological investigation should be performed promptly to ensure etiological diagnosis and optimize treatment.

Abstract Background For patients with non-small cell lung cancer (NSCLC), targeted therapies are becoming part of the standard treatment. It is of question which information the clinicians provide on test requests and how the laboratories adapt test conclusions to this knowledge and regulations. Methods This study consisted of two components; 1) checking the presence of pre-defined elements (administrative and key for therapy-choice) on completed requests and corresponding reports in Belgian laboratories, both for tissue- and liquid biopsy (LB)-testing and b) opinion analysis from Belgian pathologists/molecular biologists and clinicians during national pathology/oncology meetings. Results Data from 4 out of 6 Belgian laboratories with ISO-accreditation for LB-testing were analyzed, of which 75% were university hospitals. On the scored requests (N = 4), 12 out of 19 ISO-required elements were present for tissue and 11 for LB-testing. Especially relevant patient history, such as line of therapy (for LB), tumor histology and the reason for testing were lacking. Similarly, 11 and 9 out of 18 elements were present in the reports (N = 4) for tissue and LB, respectively. Elements that pathologists/molecular biologists (N = 18) were missing on the request were the initial activating mutation, previous therapies, a clinical question and testing-related information. For reporting, an item considered important by both groups is the clinical interpretation of the test result. In addition, clinicians (N = 28) indicated that they also wish to read the percentage of neoplastic cells. Conclusions Communication flows between the laboratory and the clinician, together with possible pitfalls were identified. Based on the study results, templates for complete requesting and reporting were proposed.

Abstract Background Circulating cell free DNA (cfDNA) testing of plasma for EGFR somatic variants in lung cancer patients is being widely implemented and with any new service, external quality assessment (EQA) is required to ensure patient safety. An international consortium, International Quality Network for Pathology (IQNPath), has delivered a second round of assessment to measure the accuracy of cfDNA testing for lung cancer and the interpretation of the results. Methods A collaboration of five EQA provider organisations, all members of IQNPath, have delivered the assessment during 2018–19 to a total of 264 laboratories from 45 countries. Bespoke plasma reference material containing a range of EGFR mutations at varying allelic frequencies were supplied to laboratories for testing and reporting according to routine procedures. The genotyping accuracy and clinical reporting was reviewed against standardised criteria and feedback was provided to participants. Results The overall genotyping error rate in the EQA was found to be 11.1%. Low allelic frequency samples were the most challenging and were not detected by some testing methods, resulting in critical genotyping errors. This was reflected in higher false negative rates for samples with variant allele frequencies (VAF) rates less than 1.5% compared to higher frequencies. A sample with two different EGFR mutations gave inconsistent detection of both mutations. However, for one sample, where two variants were present at a VAF of less than 1% then both mutations were correctly detected in 145/263 laboratories. Reports often did not address the risk that tumour DNA may have not been tested and limitations of the methodologies provided by participants were insufficient. This was reflected in the average interpretation score for the EQA being 1.49 out of a maximum of 2. Conclusions The variability in the standard of genotyping and reporting highlighted the need for EQA and educational guidance in this field to ensure the delivery of high-quality clinical services where testing of cfDNA is the only option for clinical management.

Purpose: Up to 50% of high-risk non-muscle invasive bladder cancer (HR-NMIBC) patients fail Bacillus Calmette-Guérin (BCG) treatment, resulting in a high risk of progression and poor clinical outcomes. Biomarkers that predict outcomes after BCG are lacking. The antitumor effects of BCG are driven by a cytotoxic T cell response, which may be controlled by immune checkpoint proteins like Programmed Death Ligand 1 (PD-L1). Here, we hypothesized that PD-L1 protein expression could serve as a biomarker for BCG-failure. Methods: HR-NMIBC patients who received ≥ 5 BCG instillations were included. Tissue microarrays were constructed from BCG-naïve tumors and recurrences and stained with the PD-L1 (SP142) antibody. PD-L1 status was defined as ≥ 5% tumor-infiltrating immune cells with membrane staining in the tumor area. Clinicopathological associations with PD-L1 positive tumors were investigated, and time-to-event analyses were performed comparing PD-L1 positive vs. negative tumors. Results: 432 BCG-naïve tumors and 160 recurrences were included, and 91% of patients received adequate BCG. In BCG-naïve tumors, PD-L1 was expressed in 7% of patients and PD-L1 expression was associated with stage T1 versus Ta disease (p = 0.015). PD-L1 expression was not associated with treatment failure after adequate BCG (p = 0.782) nor with progression-free survival (p = 0.732). Testing cut-offs of ≥ 1% and ≥ 10% PD-L1 positivity did not alter results. High PD-L1 expression was more frequent in tumor recurrences (14%) as compared to BCG-naïve tumors (p = 0.012). Conclusion: PD-L1 expression in HR-NMIBC is not a biomarker of response to BCG. However, PD-L1 is higher in a subset of tumors that failed BCG treatment. More research is needed to determine the role of PD-L1 in tumors where BCG treatment failed. [ABSTRACT FROM AUTHOR]

Abstract Bone surface modifications are crucial for understanding human subsistence and dietary behaviour, and can inform about the techniques employed in the production and use of bone tools. Permission to destructively sample such unique artefacts is not always granted. The recent development of non-destructive proteomic extraction techniques has provided some alternatives for the analysis of rare and culturally significant artefacts, including bone tools and personal ornaments. The Eraser Extraction Method (EEM), first developed for ZooMS analysis of parchment, has recently been applied to bone and ivory specimens. To test the potential impact of the EEM on ancient bone surfaces, we analyse six anthropogenically modified Palaeolithic bone specimens from Bacho Kiro Cave (Bulgaria) through a controlled sampling experiment using qualitative and 3D quantitative microscopy. Although the overall bone topography is generally preserved, our findings demonstrate a slight flattening of the microtopography alongside the formation of micro-striations associated with the use of the eraser for all bone specimens. Such modifications are similar to ancient use-wear traces. We therefore consider the EEM a destructive sampling approach for Palaeolithic bone surfaces. Together with low ZooMS success rates in some of the reported studies, the EEM might not be a suitable approach to taxonomically identify Pleistocene bone specimens.

Chimpanzees are traditionally described as ripe fruit specialists with large incisors but relatively small postcanine teeth, adhering to a somewhat narrow dietary niche. Field observations and isotopic analyses suggest that environmental conditions greatly affect habitat resource utilisation by chimpanzee populations. Here we combine measures of dietary mechanics with stable isotope signatures from eastern chimpanzees living in tropical forest (Ngogo, Uganda) and savannah woodland (Issa Valley, Tanzania). We show that foods at Issa can present a considerable mechanical challenge, most saliently in the external tissues of savannah woodland plants compared to their tropical forest equivalents. This pattern is concurrent with different isotopic signatures between sites. These findings demonstrate that chimpanzee foods in some habitats are mechanically more demanding than previously thought, elucidating the broader evolutionary constraints acting on chimpanzee dental morphology. Similarly, these data can help clarify the dietary mechanical landscape of extinct hominins often overlooked by broad C3/C4 isotopic categories.

Background: Telemedicine offers a promising solution to enhance the delivery and personalization of headache care. Integrating electronic (e-)tools enables the objective monitoring of migraine. Objectives: This study aims to demonstrate the relevance of e-tools for personalized headache care, assess patient and caregiver compliance and satisfaction, and present their use in enhancing care. Methods: Firstly, a systematic review was performed to validate the diagnostic accuracy of e-diaries for diagnosing migraine. Secondly, we collected e-diary data prospectively from diagnosed adult migraine patients at the Leiden Headache Center. Finally, questionnaires were sent to evaluate satisfaction of patients and health care providers with the Leiden e-headache diary and video consultations. Results: In the systematic review, the Leiden Headache Center's e-diary was the only validated tool. Patients (n = 1,009) were followed for a median of 181 days (interquartile range [IQR] 84–240). Compliance was 96.4% (IQR 85.2 − 99.1%), with 10.8% of days missing. Factors positively associated with compliance were older age (p < 0.001), female sex (p < 0.001), higher e-diary grade (p < 0.001), and clinical use (p = 0.04). The e-diary received a median score of 8/10 and was well-liked by patients (n = 535) and providers (n = 23). Video consultations were a good alternative for physical visits according to 76.9% of patients and 84.6% of providers. Conclusion: Validated e-headache diaries and video consultations in telemedicine enhance headache care accessibility, providing convenient care at preferred times and locations. [ABSTRACT FROM AUTHOR]

Abstract Background Being gifted with a very high IQ (> 98 percentile) can provide an advantage in the occupational context but can also come with its` own specific challenges. Where some studies found higher than average levels of wellbeing at work and successful careers amongst the gifted, other studies report boredom and less job satisfaction. This poses the question what gifted people value in work, and which factors are associated with the achievement of valued work related outcomes, wellbeing and sustainable employability. In this study these questions were explored using the value driven capability approach as a theoretical framework. Method A qualitative approach was chosen and 16 in-depth semi-structured interviews with gifted workers (IQ > 130) were conducted. The transcripts were analysed using a reflexive thematic analysis aimed at identifying the work related outcomes participants aspired to achieve and the contextual and personal factors that affected the actualisation of these outcomes. Results Participants placed great value on the opportunity to learn, to use their knowledge and skills, and tended to have high ethical standards. If realized, these values contributed to wellbeing whereas if not fulfilled, this often resulted in frustration and sadness. The most important personal factors associated with wellbeing at work and sustainable employability were the level of organizational awareness, self-knowledge, a willingness to compromise, and fear of stigmatisation. Contextually a facilitating leadership style of managers was important, allowing the worker autonomy and decision latitude. Socially, participants enjoyed others as sparring partners but often had an aversion to small talk which could lead to social avoidance and loneliness. Conclusions If gifted workers managed (to get) what they valued in work, this was associated with wellbeing and sustainable employment Coaching aimed at improving organizational awareness, specific social skills (e.g. small talk, adaptability) and understanding their own cognitive processes could be valuable. The application of an autonomy supporting facilitative leadership style by supervisors would be beneficial. Further research should try to confirm the findings using quantitative methods and needs to examine more closely the impact of stigmatisation and leadership styles.

Abstract Background Correct identification of the EGFR c.2369C>T p.(Thr790Met) variant is key to decide on a targeted therapeutic strategy for patients with acquired EGFR TKI resistance in non-small cell lung cancer. The aim of this study was to evaluate the correct detection of this variant in 12 tumor tissue specimens tested by 324 laboratories participating in External Quality Assessment (EQA) schemes. Methods Data from EQA schemes were evaluated between 2013 and 2018 from cell lines (6) and resections (6) containing the EGFR c.2369C>T p.(Thr790Met) mutation. Adequate performance was defined as the percentage of tests for which an outcome was available and correct. Additional data on the used test method were collected from the participants. Chi-squared tests on contingency tables and a biserial rank correlation were applied by IBM SPSS Statistics version 25 (IBM, Armonk, NY, USA). Results In 26 of the 1190 tests (2.2%) a technical failure occurred. For the remaining 1164 results, 1008 (86.6%) were correct, 151 (12.9%) were false-negative and 5 (0.4%) included incorrect mutations. Correct p.(Thr790Met) detection improved over time and for repeated scheme participations. In-house non-next-generation sequencing (NGS) techniques performed worse (81.1%, n = 293) compared to non-NGS commercial kits (85.2%, n = 656) and NGS (97.0%, n = 239). Over time there was an increase in the users of NGS. Resection specimens performed worse (82.6%, n = 610 tests) compared to cell line material (90.9%, n = 578 tests), except for NGS (96.3%, n = 344 for resections and 98.6%, n = 312 for cell lines). Samples with multiple mutations were more difficult compared to samples with the single p.(Thr790Met) variant. A change of the test method was shown beneficial to reduce errors but introduced additional analysis failures. Conclusions A significant number of laboratories that offer p.(Thr790Met) testing did not detect this relevant mutation compared to the other EQA participants. However, correct identification of this variant is improving over time and was higher for NGS users. Revising the methodology might be useful to resolve errors, especially for resection specimens with low frequency or multiple variants. EQA providers should include challenging resections in the scheme.

Abstract Background Estrogen influences susceptibility to migraine attacks and it has been suggested to affect jealousy in romantic relationships in women. Therefore, we hypothesized that migraine women may be more jealous. Methods Jealousy levels and hormonal status were determined based on a cross-sectional, web-based, questionnaire study among female migraine patients and controls. A random sample of participants was selected from a validated migraine database. Participants with a serious and intimate monogamous relationship were included (n = 498) and divided into the following subgroups: menstrual migraine (n = 167), non-menstrual migraine (n = 103), postmenopausal migraine (n = 117), and premenopausal (n = 57) and postmenopausal (n = 54) controls. The primary outcome was the difference in mean jealousy levels between patients with menstrual migraine, non-menstrual migraine and premenopausal controls. Results were analyzed with a generalized linear model adjusting for age, relationship duration and hormonal status (including oral contraceptive use). Additionally, the difference in jealousy levels between postmenopausal migraine patients and controls was assessed. Previous research was replicated by evaluating the effect of combined oral contraceptives on jealousy. Results Jealousy levels were higher in menstrual migraine patients compared to controls (mean difference ± SE: 3.87 ± 1.09, p = 0.001), and non-menstrual migraine patients compared to controls (4.98 ± 1.18, p

ObjectiveIn the field of work, there is a shift towards more value-based approaches to study the sustainable employability of the present-day worker. The capability approach offers a value based and innovative conceptualisation and framework of sustainable employability characterized by contextuality, normativity and diversity. The capabilities of Dutch employees have been established and validated, yet it is not known which conversion factors on a personal, work and organizational level enable employees to achieve value in work in different Dutch occupational sectors.MethodsOur qualitative approach included seven focus groups in different occupational sectors including elderly care, higher education, insurance work, facility management and the oil-, car- and chemical industry. Each focus group included 5-11 participants and took approximately one and a half hour. A qualitative content analysis was used to analyse the data, by combining deductive and inductive coding respectively. Deductive coding involved assigning themes to the conversion of resources into capabilities at the organizational, work and personal level.ResultsOn the organizational conversion level, important themes were cultural aspects, power relations, shortage of personnel and policies for self-management. On the work conversion level, social contacts, communication and workload, tasks and schedules were identified. Social contacts were described as a work value in itself, but also conditional for achieving other work values. On the personal conversion level, experienced work stress, motivation and the ability to achieve values informally within the company.ConclusionFrom our findings it follows that focus groups are sensitive to identify conversion factors on all three levels of conversion. In addition, companies and their employees might effectively increase work capabilities by being sensitive to all three conversion levels simultaneously. Further research is necessary to study the effect of a capability-based intervention at the work floor.