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Development and differentiation of the thyroid gland is directed by expression of specific transcription factors in the thyroid follicular cell which mediates hormone biosynthesis. Membrane transporters are rate-limiting for cellular entry of thyroid hormones (TH) (T4 and T3) into some tissues, with selenocysteine-containing, deiodinase enzymes (DIO1 and DIO2) converting T4 to the biologically active hormone T3. TH regulate expression of target genes via hormone-inducible nuclear receptors (TRα and TRβ) to exert their physiological effects. Primary congenital hypothyroidism (CH) due to thyroid dysgenesis may be mediated by defects in thyroid transcription factors or impaired thyroid stimulating hormone receptor function. Dyshormonogenic CH is usually due to mutations in genes mediating thyroidal iodide transport, organification or iodotyrosine synthesis and recycling. Disorders of TH signalling encompass conditions due to defects in membrane TH transporters, impaired hormone metabolism due to deficiency of deiodinases and syndromes of Resistance to thyroid hormone due to pathogenic variants in either TRα or TRβ. Here, we review the genetic basis, pathogenesis and clinical features of congenital, dysgenetic or dyshormonogenic hypothyroidism and disorders of TH transport, metabolism and action.

Transient congenital hypothyroidism (TCH) refers to congenital hypothyroidism which spontaneously resolves in the first few months or years of life. Currently, there is a paucity of reliable markers predicting TCH at diagnosis, and the diagnosis is established following the withdrawal of levothyroxine therapy around 3 years of age. The incidence of TCH is increasing, and it is a major contributor to the overall increase in the incidence of CH in recent studies. Both genetic factors, in particular mutations affecting DUOX2 and DUOXA2, and environmental factors, for example, iodine deficiency and excess, anti- TSHR antibodies and exposure to antithyroid or iodine-rich medications, may cause TCH. Resolution of TCH in childhood may reflect both normal thyroid physiology (decreased thyroid hormone biosynthesis requirements after the neonatal period) and clearance or cessation of environmental precipitants. The relative contributions and interactions of genetic and environmental factors to TCH, and the extent to which TCH may be prevented, require evaluation in future population-based studies.

Periconceptional maternal obesity is linked to adverse maternal and neonatal outcomes. Identifying periconceptional biomarkers of pathways affected by maternal obesity can unravel pathophysiologic mechanisms and identify individuals at risk of adverse clinical outcomes. The literature was systematically reviewed to identify periconceptional biomarkers of the endocrine, inflammatory and one-carbon metabolic pathways influenced by maternal obesity. A search was conducted in Embase, Ovid Medline All, Web of Science Core Collection and Cochrane Central Register of Controlled Trials databases, complemented by manual search in PubMed until December 31st, 2020. Eligible studies were those that measured biomarker(s) in relation to maternal obesity, overweight/obesity or body mass index (BMI) during the periconceptional period (14 weeks preconception until 14 weeks post conception). The ErasmusAGE score was used to assess the quality of included studies. Fifty-one articles were included that evaluated over 40 biomarkers. Endocrine biomarkers associated with maternal obesity included leptin, insulin, thyroid stimulating hormone, adiponectin, progesterone, free T4 and human chorionic gonadotropin. C-reactive protein was associated with obesity as part of the inflammatory pathway, while the associated one-carbon metabolism biomarkers were folate and vitamin B12. BMI was positively associated with leptin, C-reactive protein and insulin resistance, and negatively associated with Free T4, progesterone and human chorionic gonadotropin. Concerning the remaining studied biomarkers, strong conclusions could not be established due to limited or contradictory data. Future research should focus on determining the predictive value of the optimal set of biomarkers for their use in clinical settings. The most promising biomarkers include leptin, adiponectin, human chorionic gonadotropin, insulin, progesterone and CRP.

BACKGROUND: Sleep disorders, including insomnia, are widespread problems, which have increased during the COVID-19 pandemic. Guidelines for the treatment of insomnia prioritize non-pharmacological interventions. Nevertheless, primary care professionals lack well-developed material for patient education, that could help implement the treatment guidelines in Flanders, Belgium. OBJECTIVE: This project's purpose is to develop complementary, written educational material, grounded in the principles of evidence-based practice, for primary care. PATIENT INVOLVEMENT: This co-design project involved patients and health professionals. Special attention was given to including patients with low health literacy, and empowering patients when designing in mixed groups. METHODS: Based on the framework of Sanders and Stappers (2014), data were collected and analyzed in four phases. Pre-design, needs were explored using think-aloud studies and focus groups. Next, for generative purposes, the design studio method was used. Then, evaluation of the prototype happened with another series of think-aloud studies. Finally, post-design, implementation of the product was evaluated with a short survey. RESULTS: Twenty-five participants (10 patients and 15 healthcare professionals) contributed to the development of an educational patient leaflet called Sssssst. How do you sleep (at night)? Out of 30 professionals who received the printed leaflet for use in practice, 17 provided feedback after six months. Generally, the leaflet was well received. Visual design aspects stimulated use in practice. DISCUSSION: Written and visual materials aid primary care professionals to educate patients on sleep and insomnia. This supporting tool also stimulates self-management in patients. Although inspiring and educational for all stakeholders, a co-design approach is no guarantee for the product to "fit all". ispartof: PATIENT EDUCATION AND COUNSELING vol:105 issue:12 pages:3558-3565 ispartof: location:Ireland status: published

It is well known that a healthy lifestyle plays a key role in maintaining reproductive and general health, and preventing lifestyle-related diseases throughout the entire life course. Lifelong health is shaped during the preconception period and the first 1000 days of life. The importance of a healthy lifestyle during these periods can be emphasized by introducing the concept of the early life course, which covers from 100 days before conception until 1000 days thereafter. Although awareness of the benefits of a healthy lifestyle has grown, adherence is disappointing and the implementation of lifestyle interventions in medical care is scarce. Hence, we are convinced that now is the right time to turn the tide. The focus should shift from cure to prevention and promotion of health. The new concept of lifestyle care includes lifestyle interventions that support the adoption of a healthy lifestyle to optimize health and prevent lifestyle-related diseases, including subfertility and adverse pregnancy outcomes. In this paper, we advocate for the implementation of lifestyle care in medical care, define the early life course, elaborate on lifestyle care as part of lifestyle medicine, and provide examples towards the successful implementation of blended lifestyle care, which can be more widely implemented and transform medical care.

The sodium-iodide symporter (NIS, SLC5A5) is expressed at the basolateral membrane of the thyroid follicular cell, and facilitates the thyroidal iodide uptake required for thyroid hormone biosynthesis. Biallelic loss-of-function mutations in NIS are a rare cause of dyshormonogenic congenital hypothyroidism. Affected individuals typically exhibit a normally sited, often goitrous thyroid gland, with absent uptake of radioiodine in the thyroid and other NIS-expressing tissues. We report a novel homozygous NIS mutation (c.1067 C>T, p.S356F) in four siblings from a consanguineous Indian kindred, presenting with significant hypothyroidism. Functional characterization of the mutant protein demonstrated impaired plasma membrane localization and cellular iodide transport.

Funder: Sherman Foundation, Funder: NIHR Cambridge Biomedical Centre, Development and differentiation of the thyroid gland is directed by expression of specific transcription factors in the thyroid follicular cell which mediates hormone biosynthesis. Membrane transporters are rate-limiting for cellular entry of thyroid hormones (TH) (T4 and T3) into some tissues, with selenocysteine-containing, deiodinase enzymes (DIO1 and DIO2) converting T4 to the biologically active hormone T3. TH regulate expression of target genes via hormone-inducible nuclear receptors (TRα and TRβ) to exert their physiological effects. Primary congenital hypothyroidism (CH) due to thyroid dysgenesis may be mediated by defects in thyroid transcription factors or impaired thyroid stimulating hormone receptor function. Dyshormonogenic CH is usually due to mutations in genes mediating thyroidal iodide transport, organification or iodotyrosine synthesis and recycling. Disorders of TH signalling encompass conditions due to defects in membrane TH transporters, impaired hormone metabolism due to deficiency of deiodinases and syndromes of Resistance to thyroid hormone due to pathogenic variants in either TRα or TRβ. Here, we review the genetic basis, pathogenesis and clinical features of congenital, dysgenetic or dyshormonogenic hypothyroidism and disorders of TH transport, metabolism and action.

Congenital Hypothyroidism (CH) due to dyshormonogenesis may occur due to mutations in any of the key genes involved in thyroid hormone biosynthesis (TG, TPO, DUOX2, DUOXA2, SLC5A5, IYD, SLC26A4 and SLC26A7). Mutations in the Thyroglobulin gene (TG) are frequently associated with goiter, which may present fetally or neonatally, although a spectrum of phenotypes is reported. We present the case of a woman of Eritrean origin who presented in the third trimester of pregnancy in the early stages of labor. Ultrasound at presentation revealed a fetal neck swelling consistent with a goiter. Following delivery by caesarian section with minimal respiratory support, the infant was found to be hypothyroid with undetectable serum levels of thyroglobulin. Sequencing of the thyroglobulin gene revealed a homozygous donor splice site pathogenic variant (c.5686+1delG) not previously described in the literature. Levothyroxine treatment resulted in normal growth and psychomotor development. Goitrous CH with inappropriately low thyroglobulin has previously been reported in patients harbouring homozygous single nucleotide substitutions at the same TG donor splice site which result in exon skipping and Endoplasmin Reticulum retention of TG. We conclude that the TG c.5686+1delG pathogenic variant is the likely basis for our patient's fetal goiter and congenital hypothyroidism, and that the clinical phenotype associated with TG c.5686+1delG is comparable to that seen with single nucleotide substitutions at the same site.

This paper addresses the relation between two types of word order variation in two stages of Dutch: OV/VO variation in historical Dutch and scrambling in present-day Dutch. Information structural considerations influence both types of word order variation, and we demonstrate by means of a comprehensive corpus study that they have a comparable pattern: given objects tend to appear earlier in the sentence than new objects. We infer from this that the two types of word order variation are diachronically related. Our findings support an analysis of scrambling as object movement from a uniformly head-initial base via the specifier of VP to the specifier ofvP. We argue that historical Dutch allows spell out of the object in its postverbal base position, but that this possibility was eventually lost. Consequently, the boundary between the given and new domains shifts from the verb to the adverbial.

Patients taking a medicinal product in a homecare setting typically use a medical device to facilitate the injection process. Reductions in wireless connectivity costs, combined with the rapid adoption of smartphones with connectivity to cloud-based services, are enabling these drug delivery devices to now be connected to a digital ecosystem as connected combined products (CCPs). The purposes of this article are to identify the challenges in developing and releasing these products when they straddle different regulatory frameworks and standards and to highlight gaps in the European Union regulations.Industry subject matter experts from pharmaceutical, medical device, and consultancy companies, who are members of the MedtechPharma Platform Association, formed 4 working groups to address current best practice for developing and releasing CCPs and the different relevant regulatory frameworks. The 4 areas studied were clinical and regulatory, usability and human factors engineering, development and life cycle management, and cybersecurity.Development teams require new skills to create innovative products that have a good safety profile and are simple to use, such as design thinking to understand user needs and systems engineering to manage complexity and ensure interoperability. Risk management process should integrate cybersecurity, data privacy, and data integrity, whereas design control processes should enable asynchronous development cycles for hardware and software components. Regulatory frameworks exist for individual components within the CCP. However, for a complex product, regulatory guidance is needed when combining components with different risk and safety profiles and to ensure that the responsibilities and liabilities of companies contributing components are clear. The efficient management of software changes and product updates, as well as dealing with end-of-life hardware and backward compatibility to older software versions, needs agile approaches when it comes to regulatory updates.The regulatory uncertainties and development processes outlined in this article need to be addressed. We call for joint discussions among the various stakeholders in the fields of medicinal products, medical devices, and in vitro diagnostics, as well as standalone software, data protection, and cybersecurity experts, together with regulators and lawmakers in the European Union to meet in focused discussion groups with the aim of devising pragmatic solutions and regulations for the benefit of the sector and hence the patients it serves.

Applied and environmental microbiology (2023). doi:10.1128/aem.00078-23, Published by American Society for Microbiology, Washington, DC [u.a.]

Background: To support self-management of chronically ill persons, innovative approaches of care practice are being developed. Unfortunately, many self-management supporting interventions struggle to achieve reliable and consistent improvements at various levels (patient, provider and healthcare system level). One possible strategy to facilitate translating theory into practice, is to consider the healthcare professionals’ perspective prior to the development of new interventions. An exploration of their knowledge and opinion about barriers and facilitators is necessary before employing any self-management support (SMS) intervention. Therefore, our study aims to explore care professionals’ perspectives about SMS within the Flemish primary care setting. Methods: This study used a qualitative study design to examine SMS in primary care setting. Five focus groups were conducted, grouped into three waves. Participants were healthcare professionals in Flanders representing different disciplines and settings. A maximum variation purposive sampling was used to recruit participants. For the data analysis, the framework of thematic networks by Attride-Stirling was applied. Results: A total of 34 healthcare professionals participated. Three global themes related to SMS were derived from the thematic analysis: (1) Characteristics, (2) Support strategies, (3) Barriers and facilitators. SMS was characterised as a collaboration-based and person-centred approach. A variety of supporting strategies were mentioned by the focus group participants. Most strategies consisted of informing and educating patients. Complementary to individual strategies, collaborative strategies were deemed necessary to support self-management. Regarding barriers and facilitators, different patient-related factors were identified. Additionally, competencies of healthcare providers and external factors seem to hinder the implementation of SMS in practice. Conclusions: This focus group study highlights the importance of a collaborative, person-centred approach to SMS in the context of chronic diseases. Our findings point to the need for interventions that raise awareness and address barriers associated with SMS. Since generic SMS does not exist, the road to success is a growth process in which support must be adapted to the individual patient.

Background Belongingness has been proposed as a potential proxy for legitimate peripheral participation in medical education. Previous studies have shown good internal and external validity for tools designed to measure this variable, with potential use measuring the effectiveness of clinical teaching environments. This study examined changes in belongingness in medical students between 2019 and 2021 during covid related restrictions, and compared levels of belongingness in medical students in Belgium and the United Kingdom. Methods This study used a validated assessment tool that was self-administered via an online survey platform. Anonymised data was collected from undergraduate medical students from all years of training and results compared with previous data collected in 2019. Results The belongingness assessment tool described here good internal and external validity in undergraduate medical students in United Kingdom and Belgium, identified statistically significant changes in Belongingness (as measured with this tool) in undergraduate medical students during Covid restrictions and identified statistically significant differences between medical students in Belgium and the United Kingdom. Conclusions These results suggest that belongingness in in undergraduate medical students fluctuates and varies both between different demographic groups and under different conditions. The ability to measure this key facet of educational development has potential to monitor teaching environments to ensure optimal learning conditions for all students.

Background In view of the exponential use of the CanMEDS framework along with the lack of rigorous evidence about its applicability in workplace-based medical trainings, further exploring is necessary before accepting the framework as accurate and reliable competency outcomes for postgraduate medical trainings. Therefore, this study investigated whether the CanMEDS key competencies could be used, first, as outcome measures for assessing trainees’ competence in the workplace, and second, as consistent outcome measures across different training settings and phases in a postgraduate General Practitioner’s (GP) Training. Methods In a three-round web-based Delphi study, a panel of experts (n = 25–43) was asked to rate on a 5-point Likert scale whether the CanMEDS key competencies were feasible for workplace-based assessment, and whether they could be consistently assessed across different training settings and phases. Comments on each CanMEDS key competency were encouraged. Descriptive statistics of the ratings were calculated, while content analysis was used to analyse panellists’ comments. Results Out of twenty-seven CanMEDS key competencies, consensus was not reached on six competencies for feasibility of assessment in the workplace, and on eleven for consistency of assessment across training settings and phases. Regarding feasibility, three out of four key competencies under the role “Leader”, one out of two competencies under the role “Health Advocate”, one out of four competencies under the role “Scholar”, and one out of four competencies under the role “Professional” were deemed as not feasible for assessment in a workplace setting. Regarding consistency, consensus was not achieved for one out of five competencies under “Medical Expert”, two out of five competencies under “Communicator”,one out of three competencies under “Collaborator”, one out of two under “Health Advocate”, one out of four competencies under “Scholar”, one out of four competencies under “Professional”. No competency under the role “Leader” was deemed to be consistently assessed across training settings and phases. Conclusions The findings indicate a mismatch between the initial intent of the CanMEDS framework and its applicability in the context of workplace-based assessment. Although the CanMEDS framework could offer starting points, further contextualization of the framework is required before implementing in workplace-based postgraduate medical trainings.

Supplementary Figure 7 from Integrated Profiling of Basal and Luminal Breast Cancers

Supplementary Table 2 from Genome-Wide Array-Based Comparative Genomic Hybridization Reveals Multiple Amplification Targets and Novel Homozygous Deletions in Pancreatic Carcinoma Cell Lines

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Supplementary Figure 1B from Integrated Profiling of Basal and Luminal Breast Cancers

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Supplementary Figure 4 from Integrated Profiling of Basal and Luminal Breast Cancers

Basal and luminal are two molecular subtypes of breast cancer with opposite histoclinical features. We report a combined, high-resolution analysis of genome copy number and gene expression in primary basal and luminal breast cancers. First, we identified and compared genomic alterations in 45 basal and 48 luminal tumors by using 244K oligonucleotide array comparative genomic hybridization (aCGH). We found various genome gains and losses and rare high-level gene amplifications that may provide therapeutic targets. We show that gain of 10p is a new alteration in basal breast cancer and that a subregion of the 8p12 amplification is specific of luminal tumors. Rare high-level amplifications contained BCL2L2, CCNE, EGFR, FGFR2, IGF1R, NOTCH2, and PIK3CA. Potential gene breaks involved ETV6 and FLT3. Second, we analyzed both aCGH and gene expression profiles for 42 basal and 32 luminal breast cancers. The results support the existence of specific oncogenic pathways in basal and luminal breast cancers, involving several potential oncogenes and tumor suppressor genes (TSG). In basal tumors, 73 candidate oncogenes were identified in chromosome regions 1q21-23, 10p14, and 12p13 and 28 candidate TSG in regions 4q32-34 and 5q11-23. In luminal breast cancers, 33 potential oncogenes were identified in 1q21-23, 8p12-q21, 11q13, and 16p12-13 and 61 candidate TSG in 16q12-13, 16q22-24, and 17p13. HORMAD1 (P = 6.5 × 10−5) and ZNF703 (P = 7 × 10−4) were the most significant basal and luminal potential oncogenes, respectively. Finally, among 10p candidate oncogenes associated with basal subtype, we validated CDC123/C10orf7 protein as a basal marker. [Cancer Res 2007;67(24):11565–75]

Supplementary Figure 9 from Integrated Profiling of Basal and Luminal Breast Cancers

Supplementary Figure 2 from Integrated Profiling of Basal and Luminal Breast Cancers

Supplementary Figure 1D from Integrated Profiling of Basal and Luminal Breast Cancers

Supplementary Figure 1A from Integrated Profiling of Basal and Luminal Breast Cancers

Supplementary Tables 1-9 from Integrated Profiling of Basal and Luminal Breast Cancers

Pancreatic carcinomas display highly complex chromosomal abnormalities, including many structural and numerical aberrations. There is ample evidence indicating that some of these abnormalities, such as recurrent amplifications and homozygous deletions, contribute to tumorigenesis by altering expression levels of critical oncogenes and tumor suppressor genes. To increase the understanding of gene copy number changes in pancreatic carcinomas and to identify key amplification/deletion targets, we applied genome-wide array-based comparative genomic hybridization to 31 pancreatic carcinoma cell lines. Two different microarrays were used, one containing 3,565 fluorescence in situ hybridization-verified bacterial artificial chromosome clones and one containing 25,468 cDNA clones representing 17,494 UniGene clusters. Overall, the analyses revealed a high genomic complexity, with several copy number changes detected in each case. Specifically, 60 amplicons at 32 different locations were identified, most frequently located within 8q (8 cases), 12p (7 cases), 7q (5 cases), 18q (5 cases), 19q (5 cases), 6p (4 cases), and 8p (4 cases). Amplifications of 8q and 12p were mainly clustered at 8q23–24 and 12p11–12, respectively, whereas amplifications on other chromosome arms were more dispersed. Furthermore, our analyses identified several novel homozygously deleted segments located to 9p24, 9p21, 9q32, 10p12, 10q22, 12q24, and 18q23. The individual complexity and aberration patterns varied substantially among cases, i.e., some cell lines were characterized mainly by high-level amplifications, whereas others showed primarily whole-arm imbalances and homozygous deletions. The described amplification and deletion targets are likely to contain genes important in pancreatic tumorigenesis.

Supplementary Materials from Integrated Profiling of Basal and Luminal Breast Cancers

Supplementary Figure 5 from Integrated Profiling of Basal and Luminal Breast Cancers

Supplementary Figure 6 from Integrated Profiling of Basal and Luminal Breast Cancers

Introduction Since 2000, an increasing misuse of emergency services in Belgium was noticed. In 2015, a multidisciplinary task-force designed a triage system. Trained operators and integrated triage protocols were installed in a call center for life-threatening and non-life-threatening care needs. Teleconsultations by telephone find their way to planned care and are well studied in this context. Also unplanned care might benefit from telephone-consultations. Method This intervention study investigated the feasibility of teleconsultations in unplanned care according to medical doctors. They were present at the call center during the weekend and on public holidays in the period of April 17, 2021 to November 21, 2021. Their task was to call patients who had contacted the call center to perform a teleconsultation, without interfering with regular care. Results 21 triage doctors participated in the study, they completed 59 surveys and conducted 551 teleconsultations. They perceived the quality of the consultations as good with an average score of 82.85 out of 100 on the sliding scale. The doctors gave an average score of 72.40 for the level of certainty for diagnosis and treatment. For 415 consultations, triage doctors judged that the consultation would gain certainty if followed by a physical examination. Video was mainly considered to be valuable in psychiatric problems, allergic reactions and skin problems. Discussion This study showed that teleconsultations are feasible in unplanned care. Videos add value in particular cases. Only few barriers are reported in terms of communication, technology and equipment. Conclusion Teleconsultations in unplanned primary care could be performed with a high quality and a sufficient level of certainty. The willingness to conduct teleconsultations in unplanned care is high. It would be useful in a future study to investigate the feasibility, obstacles and needs for implementation of video consultations as they may differ from teleconsultations.

Background Experience and research show that screening for malnutrition in primary care mainly takes place by monitoring the weight parameter and that validated screening instruments are hardly used. In this study we examined the effectiveness and predictive value of weight evolution in screening for (risk of) malnutrition in older people living at home, in comparison with a validated screening tool, namely the Mini Nutritional Assessment Short Form (MNA-SF). Methods This project was a prospective, longitudinal study with quantitative data that took place in the province of Antwerp (Belgium) from December 2020 until June 2021. The target group of this study consisted of people over 70 living at home who were visited by a home nurse on a regular basis (at least once a month). The outcome measure was the weight evolution over six months compared with the score on the MNA-SF at month six. Weight was measured and recorded once a month during 6 months. At the last weight measurement, the MNA-SF was administered. In order to assess their own nutritional state, three additional questions were asked after taking the MNA-SF. Results A total of 143 patients gave consent to participate, of which 89 were women and 54 men. The mean age was 83.7 years (SD6.62) with a range of 70 to 100 years. Based on the MNA-SF score measured after six months, 53.1% (76/143) of participants had a normal nutritional status, 37.8% (54/143) scored risk of malnutrition and 4.9% (7/ 143) was malnourished. In order to detect people with (risk of) malnutrition, a PPV of 78.6%, a NPV of 60.7%, a sensitivity of 19.3% and a specificity of 96.0% were established with a weight evolution of ≥ 5% weight loss at six months. To detect malnutrition, our results showed respectively 33.3%, 98.4%, 71.4% and 92.3%. Conclusion In this study, weight evolution has a low sensitivity in screening for (risk of) malnutrition in people over 70 living at home compared to the MNA-SF. However, in order to detect people with malnutrition, this study demonstrated a sensitivity of 71.4% and a specificity of 92.3% for a weight loss of ≥ 5% at six months.

Infections by meningococcal species are extremely rare in the first days of life. We present a fatal case of early-onset sepsis presenting at birth, caused by intrauterine transmission of serogroup Y N. meningitidis, evidenced clinically and histologically by corresponding chorioamnionitis and N. meningitidis-positive amniotic fluid. This case confirms a long-standing suspicion that N. meningitidis can be transmitted in utero.

In this work, devices for two-dimensional separations are considered. The device contains a flow distributor, a first-dimension channel, and 17 second-dimension outlets. In the design, all connections between the first-dimension channel, the flow distributor, and the second-dimension outlets were tapered, with a minimal diameter of 20 μm. The use of photo-masking is explored for the fabrication of monolithic frits in all tapered connections. Monolithic frits with optimized permeability and length were successfully fabricated in all 33 tapered channels through light-induced polymerization, photo-masking, and selective exposure. The efficacy of the monolithic frits was demonstrated by creating a packed bed of 15-μm particles, confined within the first-dimension channel. The outlet of the first-dimension channel was successfully connected to a mass spectrometer. Effective flow confinement was demonstrated with a reversed-phase separation of a mixture of five standard peptides.

In recent years, loneliness has been receiving increasing attention, yet there remains a lot to learn about how older adults cope with loneliness. In this study, the practices older adults consider for coping with loneliness and the relationship between various types of coping practices, loneliness, and personal resources are examined. Several hypotheses about the relationship between social and emotional loneliness, personal resources, and mentioning coping practices are formulated. Data was collected in Gipuzkoa (Basque Country, Spain) through structured interviews using a telephone survey among a representative sample of older adults aged 55 and over (

Implantation is a critical step in human reproduction. The success of this step is dependent on a competent blastocyst, receptive endometrium, and successful cross talk between the embryonic and maternal interfaces. Recurrent implantation failure is the lack of implantation after the transfer of several embryo transfers. As the success of in vitro fertilization has increased and failures have become more unacceptable for patients and providers, the literature on recurrent implantation failure has increased. While this clinical phenomenon is often encountered, there is not a universally agreed-on definition—something addressed in an earlier portion of this Views and Reviews. Implantation failure can result from several different factors. In this review, we discuss factors including the maternal immune system, genetics of the embryo and parents, anatomic factors, hematologic factors, reproductive tract microbiome, and endocrine milieu, which factors into embryo and endometrial synchrony. These potential causes are at various stages of research and not all have clear implications or immediately apparent treatment.

Background: The leukodystrophy “Vanishing White Matter” (VWM) is an orphan disease with neurological decline and high mortality. Currently, VWM has no approved treatments, but advances in understanding pathophysiology have led to identification of promising therapies. Several investigational medicinal products are either in or about to enter clinical trial phase. Clinical trials in VWM pose serious challenges, as VWM has an episodic disease course; disease phenotype is highly heterogeneous and predictable only for early onset; and study power is limited by the small patient numbers. To address these challenges and accelerate therapy delivery, the VWM Consortium, a group of academic clinicians with expertise in VWM, decided to develop a core protocol to function as a template for trials, to improve trial design and facilitate sharing of control data, while permitting flexibility regarding other trial details. Overall aims of the core protocol are to collect safety, tolerability, and efficacy data for treatment assessment and marketing authorization. Methods: To develop the core protocol, the VWM Consortium designated a committee, including clinician members of the VWM consortium, family and patient group advocates, and experts in statistics, clinical trial design and alliancing with industries. We drafted three age-specific protocols, to stratify into more homogeneous patient groups, of ages ≥18 years, ≥6 to Discussion: The core protocol provides a shared uniformity across trials, enables a pool of shared controls, and reduces the total number of patients necessary per trial, limiting the number of patients on placebo. All VWM clinical trials are suggested to adhere to the core protocol. Other trial components such as choice of primary outcome, pharmacokinetics, pharmacodynamics, and biomarkers are flexible and unconstrained by the core protocol. Each sponsor is responsible for their trial execution, while the control data are handled by a shared research organization. This core protocol benefits the efficiency of parallel and consecutive trials in VWM, and we hope accelerates time to availability of treatments for VWM. Trial registration: NA

Extreme response style (ERS), the tendency of participants to select extreme item categories regardless of the item content, has frequently been found to decrease the validity of Likert-type questionnaire results (Moors, 2012). For this reason, various IRT models have been proposed to model ERS and correct for it. Comparisons of these models are however rare in the literature, especially in the context of cross-cultural comparisons, where ERS is even more relevant due to cultural differences between groups. To remedy this issue, the current paper examines two frequently used IRT models that can be estimated using standard software: a multidimensional nominal response model (MNRM) and a IRTree model. Studying conceptual differences between these models reveals that they differ substantially in their conceptualization of ERS. These differences result in different category probabilities between the models. To evaluate the impact of these differences in a multigroup context, a simulation study is conducted. Our results show that when the groups differ in their average ERS, the IRTree model and MNRM can drastically differ in their conclusions about the size and presence of differences in the substantive trait between these groups. Implications for the future use of both models and the conceptualization of ERS are discussed.

IntroductionTo investigate whether biochemical and haematological changes due to the patient’s host response (CoLab algorithm) in combination with a SARS-CoV-2 viability PCR (v-PCR) can be used to determine when a patient with COVID-19 is no longer infectious.We hypothesise that the CoLab algorithm in combination with v-PCR can be used to determine whether or not a patient with COVID-19 is infectious to facilitate the safe release of patients with COVID-19 from isolation.Methods and analysisThis study consists of three parts using three different cohorts of patients. All three cohorts contain clinical, vital and laboratory parameters, as well as logistic data related to isolated patients with COVID-19, with a focus on intensive care unit (ICU) stay. The first cohort will be used to develop an algorithm for the course of the biochemical and haematological changes of the host response of the COVID-19 patient. Simultaneously, a second prospective cohort will be used to investigate the algorithm derived in the first cohort, with daily measured laboratory parameters, next to conventional SARS-CoV-2 reverse transcriptase PCRs, as well as v-PCR, to confirm the presence of intact SARS-CoV-2 particles in the patient. Finally, a third multicentre cohort, consisting of retrospectively collected data from patients with COVID-19 admitted to the ICU, will be used to validate the algorithm.Ethics and disseminationThis study was approved by the Medical Ethics Committee from Maastricht University Medical Centre+ (cohort I: 2020-1565/300523) and Zuyderland MC (cohorts II and III: METCZ20200057). All patients will be required to provide informed consent. Results from this study will be disseminated via peer-reviewed journals and congress/consortium presentations.

Background Lifestyle behaviors during the periconception period contribute to achievement of a successful pregnancy. Assessment of attitudes and practices toward these modifiable behaviors can aid in identifying gaps in unhealthy lifestyle behaviors with impact on intervention effectiveness. Objective This study investigates the effectiveness of coaching by the eHealth program Smarter Pregnancy during the periconception period on improvement of attitudes and practices toward fruit and vegetable intake and smoking in women attempting pregnancy through assisted reproductive technology (ART) or natural conception. Methods Women attempting pregnancy through ART (n=1060) or natural conception (n=631) were selected during the periconception period. The intervention groups, conceived through ART or naturally, received Smarter Pregnancy coaching for 24 weeks, whereas the control group conceived through ART and did not receive coaching. Attitudes and practices at baseline and follow-up periods were obtained from self-administered online questionnaire provided by the program. Attitudes were assessed in women with unhealthy behaviors as their intention to increase their fruit and vegetable intake and to quit smoking using a yes/no question. Outcomes on practices, suggesting effectiveness, included daily fruit (pieces) and vegetable (grams) intake, and if women smoked (yes/no). Changes in attitudes and practices were compared at 12 and 24 weeks with baseline between the ART intervention and ART control groups, and within the intervention groups between ART and natural conception. Changes in practices at 12 and 24 weeks were also compared with baseline between women with negative attitude and positive attitude within the intervention groups: ART and natural conception. Analysis was performed using linear and logistic regression models adjusted for maternal confounders and baseline attitudes and practices. Results The ART intervention group showed higher vegetable intake and lower odds for negative attitudes toward vegetable intake after 12 weeks (βadj=25.72 g, P Conclusions The eHealth Smarter Pregnancy program may improve vegetable intake–related attitudes and practices in women undergoing ART treatment. Women with no intention to increase fruit and vegetable intake had less improvement in their intakes. Despite small changes, this study demonstrates again that Smarter Pregnancy can be used to improve vegetable intake, which can complemented by blended care that combines face-to-face and online care to also improve fruit intake and smoking behavior.

Supplemental material, sj-pdf-1-epm-10.1177_00131644231155838 for Correcting for Extreme Response Style: Model Choice Matters by Martijn Schoenmakers, Jesper Tijmstra, Jeroen Vermunt and Maria Bolsinova in Educational and Psychological Measurement

Supplementary Material 1

Item does not contain fulltext The COVID-19 pandemic had a major psychological impact on society, particularly affecting its vulnerable members including pregnant women and their (un)born children. Moreover, accumulating evidence indicates that maternal stress can have lifelong effects on the unborn child. Accordingly, pregnant women's vulnerability for mental health problems has become a concern during the COVID-19 pandemic. This chapter highlights the psychological impact of the COVID-19 pandemic on pregnant women and the potential short- and long-term consequences for their offspring. An overview is provided of the effects of prenatal maternal stress caused by previous disasters. Moreover, potential mechanisms are discussed of fetal programming and transgenerational effects of maternal prenatal stress. We conclude that the lessons learned from experiences with previous disasters should quickly be applied to the current COVID-19 pandemic. Close monitoring of offspring after prenatal stress due to the COVID-19 pandemic is necessary to detect and effectively target vulnerable developmental windows and divert adverse outcomes later during the life course.