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Abstract Background While successful information transfer and seamless medication supply are fundamental to medication safety during hospital-to-home transitions, disruptions are frequently reported. In Germany, new legal requirements came into force in 2017, strengthening medication lists and discharge summaries as preferred means of information transfer. In addition to previous regulations – such as dispensing medication at discharge by hospital pharmacies – hospital physicians were now allowed to issue discharge prescriptions to be supplied by community pharmacies. The aim of this survey study was to gain first nationwide insights into how these requirements are implemented and how they impact the continuity of medication information transfer and continuous medication supply. Methods Two nationwide self-administered online surveys of all hospital and community pharmacies across Germany were developed and conducted from April 17th to June 30th, 2023. Results Overall, 31.0% (n = 111) of all German hospital pharmacies and 4.5% (n = 811) of all community pharmacies participated. The majority of those hospital pharmacies reported that patients who were discharged were typically provided with discharge summaries (89.2%), medication lists (59.5%) and if needed, discharge prescriptions (67.6%) and/or required medication (67.6%). About every second community pharmacy (49.0%) indicated that up to half of the recently discharged patients who came to their pharmacy typically presented medication lists. 34.0% of the community pharmacies stated that they typically received a discharge summary from recently discharged patients at least once per week. About three in four community pharmacies (73.3%) indicated that most discharge prescriptions were dispensed in time. However, one-third (31.0%) estimated that half and more of the patients experienced gaps in medication supply. Community pharmacies reported challenges with the legal requirements – such as patients´ poor comprehensibility of medication lists, medication discrepancies, unmet formal requirements of discharge prescriptions, and poor accessibility of hospital staff in case of queries. In comparison, hospital pharmacies named technical issues, time/personnel resources, and deficits in patient knowledge of medication as difficulties. Conclusion According to the pharmacies´ perceptions, it can be assumed that discontinuation in medication information transfer and lack of medication supply still occur today during hospital-to-home transitions, despite the new legal requirements. Further research is necessary to supplement these results by the perspectives of other healthcare professionals and patients in order to identify efficient strategies.

Abstract Micro- and nanoplastics (MNPs) are ubiquitous environmental pollutants representing a concern for human health. MNPs have been detected in human placentas, indicating that during pregnancy maternal exposure may lead to placental transfer and foetal exposure, with potential for adverse effects on early-life development. However, a comprehensive risk assessment (RA) framework, specific to early-life is lacking. Here, we propose a novel roadmap to assist the development of an early-life health RA of MNPs. This roadmap is designed based on established chemical, mixture, particle, and MNP assessment strategies aligned with standard RA components (problem formulation, hazard identification, hazard characterisation, exposure assessment, risk characterisation). We systematically work through these stages to identify what is needed to progress a RA for the early-life impacts of MNPs, including what information is missing, and what may be used in the interim. While challenges such as complex physicochemical properties of MNPs, limited toxicity data at relevant exposure levels, and uncertainties related to characterising complex exposures have been described elsewhere, our work discusses how these challenges specifically impact early-life stages such as the significance of MNP presence in biological samples and factors influencing bioaccumulation and placental transfer. Additionally, we introduce the development of new technology readiness levels for methods used in the detection of MNPs in complex matrices. Importantly, this review integrates a broad scope of relevant information into one comprehensive document, providing a unified resource. We highlight specific requirements and areas for targeted research, including the development of dose-response relationships specific to early-life stages and novel strategies for assessing bioaccumulation and placental transfer of MNPs. By addressing these gaps, our roadmap aims to advance the development of a robust framework, ultimately enhancing the understanding and mitigation of risks associated with early-life exposure to MNPs.

Abstract The application of supervised machine learning methods to identify behavioural modes from inertial measurements of bio-loggers has become a standard tool in behavioural ecology. Several design choices can affect the accuracy of identifying the behavioural modes. One such choice is the inclusion or exclusion of segments consisting of more than a single behaviour (mixed segments) in the machine learning model training data. Currently, the common practice is to ignore such segments during model training. In this paper we tested the hypothesis that including mixed segments in model training will improve accuracy, as the model would perform better in identifying them in the test data. We test this hypothesis using a series of data simulations on four datasets of accelerometer data coupled with behaviour observations, obtained from four study species (Damaraland mole-rats, meerkats, olive baboons, polar bears). Results show that when a substantial proportion of the test data are mixed behaviour segments (above ~ 10%), including mixed segments in machine learning model training improves the accuracy of classification. These results were consistent across the four study species, and robust to changes in segment length, sample size, and degree of mixture within the mixed segments. However, we also find that in some cases (particularly in baboons) models trained with mixed segments show reduced accuracy in classifying test data containing only single behaviour (pure) segments, compared to models trained without mixed segments. Based on these results, we recommend that when the classification model is expected to deal with a substantial proportion of mixed behaviour segments (> 10%), it is beneficial to include them in model training, otherwise, it is unnecessary but also not harmful. The exception is when there is a basis to assume that the training data contains a higher rate of mixed segments than the actual (unobserved) data to be classified—such a situation may occur particularly when training data are collected in captivity and used to classify data from the wild. In this case, excess inclusion of mixed segments in training data should probably be avoided.

Abstract Novel methods for sampling and characterizing biodiversity hold great promise for re-evaluating patterns of life across the planet. The sampling of airborne spores with a cyclone sampler, and the sequencing of their DNA, have been suggested as an efficient and well-calibrated tool for surveying fungal diversity across various environments. Here we present data originating from the Global Spore Sampling Project, comprising 2,768 samples collected during two years at 47 outdoor locations across the world. Each sample represents fungal DNA extracted from 24 m3 of air. We applied a conservative bioinformatics pipeline that filtered out sequences that did not show strong evidence of representing a fungal species. The pipeline yielded 27,954 species-level operational taxonomic units (OTUs). Each OTU is accompanied by a probabilistic taxonomic classification, validated through comparison with expert evaluations. To examine the potential of the data for ecological analyses, we partitioned the variation in species distributions into spatial and seasonal components, showing a strong effect of the annual mean temperature on community composition.

Abstract Background Genetic abnormalities in the FGFR signalling occur in 40% of breast cancer (BCa) patients resistant to anti-ER therapy, which emphasizes the potential of FGFR-targeting strategies. Recent findings indicate that not only mutated FGFR is a driver of tumour progression but co-mutational landscapes and other markers should be also investigated. Autophagy has been recognized as one of the major mechanisms underlying the role of tumour microenvironment in promotion of cancer cell survival, and resistance to anti-ER drugs. The selective autophagy receptor p62/SQSTM1 promotes Nrf-2 activation by Keap1/Nrf-2 complex dissociation. Herein, we have analysed whether the negative effect of FGFR2 on BCa cell response to anti-ER treatment involves the autophagy process and/or p62/Keap1/Nrf-2 axis. Methods The activity of autophagy in ER-positive MCF7 and T47D BCa cell lines was determined by analysis of expression level of autophagy markers (p62 and LC3B) and monitoring of autophagosomes’ maturation. Western blot, qPCR and proximity ligation assay were used to determine the Keap1/Nrf-2 interaction and Nrf-2 activation. Analysis of 3D cell growth in Matrigel® was used to assess BCa cell response to applied treatments. In silico gene expression analysis was performed to determine FGFR2/Nrf-2 prognostic value. Results We have found that FGFR2 signalling induced autophagy in AMPKα/ULK1-dependent manner. FGFR2 activity promoted dissociation of Keap1/Nrf-2 complex and activation of Nrf-2. Both, FGFR2-dependent autophagy and activation of Nrf-2 were found to counteract the effect of anti-ER drugs on BCa cell growth. Moreover, in silico analysis showed that high expression of NFE2L2 (gene encoding Nrf-2) combined with high FGFR2 expression was associated with poor relapse-free survival (RFS) of ER+ BCa patients. Conclusions This study revealed the unknown role of FGFR2 signalling in activation of autophagy and regulation of the p62/Keap1/Nrf-2 interdependence, which has a negative impact on the response of ER+ BCa cells to anti-ER therapies. The data from in silico analyses suggest that expression of Nrf-2 could act as a marker indicating potential benefits of implementation of anti-FGFR therapy in patients with ER+ BCa, in particular, when used in combination with anti-ER drugs. Graphical Abstract

Abstract Background The first COVID-19 wave in 2020 necessitated temporary suspension of non-essential medical services including organized cancer screening programs in Belgium. This study assessed the impact of the pandemic on breast cancer (BC) incidence, stage at diagnosis, and management in Belgium in 2020. Methods All Belgian residents diagnosed with in situ or invasive BC in 2015–2020 in the nationwide, population-based cancer registry database were included. Incidence trends for 2015–2019 were extrapolated to predict incidence and stage distribution for 2020 and compared with the observed values. National healthcare reimbursement data were used to examine treatment strategies. Exact tumor diameter and nodal involvement, extracted from pathology reports, were analyzed for 2019 and 2020. Results 74,975 tumors were selected for analysis of incidence and clinical stage. Invasive BC incidence declined by -5.0% in 2020, with a drop during the first COVID-19 wave (Mar-Jun; -23%) followed by a rebound (Jul-Dec; +7%). Predicted and observed incidence (in situ + invasive) was not different in patients

Abstract Background Sick-leave rates are high due to stress-related illnesses, but little is still known about the process of recovery from these conditions. The aim of this study was to explore the experiences of the recovery process, 6 to 10 years after treatment in people previously diagnosed with exhaustion disorder (ED), focusing on facilitators and barriers for the process of recovery from ED, and recovery activities experienced as helpful during the recovery process. Method Thirty-eight participants (average age: 52 years, 32 females) previously diagnosed with ED were interviewed with semi-structured interviews 6–10 years after undergoing treatment. The interviews were analyzed with thematic analysis. Results Three themes resulted from the analysis. The first theme, “A long and rocky road”, summarizes the fluctuating path to feeling better and emphasizes barriers and facilitators that affected the process of recovery, with a focus on external life events and the participants’ own behaviors. Facilitators were changing workplace, receiving support, a reduction in stressors, and changed behaviors. Barriers were a poor work environment, caregiver responsibilities, negative life events and lack of support. The second theme “Recovery activities are needed every step of the way” describes how both the need for recovery activities and the types of activities experienced as helpful changed during the recovery process, from low-effort recovery activities for long periods of time to shorter and more active recovery activities. Recovery activities were described as important for self-care but hard to prioritize in everyday life. The last theme, “Reorienting to a new place”, captures the struggle to cope with the remaining impact of ED, and how internal facilitators in terms of understanding and acceptance were important to reorient and adjust to a new way of functioning. Conclusions Recovering from ED is a long and ongoing process where recovery activities are needed every step of the way. Our results highlight the importance of supporting personal recovery and long-term behavioral change, addressing individual stressors that may perpetuate the condition, and adjusting recovery activities according to where the person is in the recovery process. Trial registration ClinicalTrials.gov: NCT0073772 . Registered on March 8, 2017. This study was pre-registered on Open Science Framework (osf.io).

Background: Hepatitis B infection is a significant global health threat contributing to healthcare worker (HCW) harm, threatening already precarious health systems. Aim: To document self-reported hepatitis B vaccination history and serology results. Setting: A select group of high-risk HCWs in a tertiary care hospital in Banjul, the Gambia. Methods: This was a cross-sectional pilot study conducted from 12 June 2023 to 16 June 2023. Participants were HCWs at high risk for blood exposure who completed a health history interview prior to serology testing for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) and vaccination. Results: The pilot study enrolled 70 HCWs who were primarily female (n = 44; 62.9%). The majority of the participants, 43 (61.4%) reported having received at least one dose of the hepatitis B vaccine in the past. The overall prevalence of HBsAg positivity in this study was 4.3% (95% confidence interval [CI]: 1.5–11.9), all in older participants. Importantly, 60.0% (95% CI: 48.3–70.7) of participants had no anti-HBs detected. Conclusion: This pilot study documents a higher prevalence of hepatitis B infection among older workers and the lack of anti-HBs across the majority of participants. This suggests a serious vulnerability for the individual health worker and indicates the need for a wider screening and vaccination campaign to assess the risk across the Gambian health workforce. Contribution: This pilot study provides the first evidence to support a wider assessment of hepatitis B serology status of Gambian health workers to gauge the need for a broader vaccine campaign.

Abstract Lyme disease is a tick-borne disease caused by bacteria of the genus Borrelia. The host factors that modulate susceptibility for Lyme disease have remained mostly unknown. Using epidemiological and genetic data from FinnGen and Estonian Biobank, we identify two previously known variants and an unknown common missense variant at the gene encoding for Secretoglobin family 1D member 2 (SCGB1D2) protein that increases the susceptibility for Lyme disease. Using live Borrelia burgdorferi (Bb) we find that recombinant reference SCGB1D2 protein inhibits the growth of Bb in vitro more efficiently than the recombinant protein with SCGB1D2 P53L deleterious missense variant. Finally, using an in vivo murine infection model we show that recombinant SCGB1D2 prevents infection by Borrelia in vivo. Together, these data suggest that SCGB1D2 is a host defense factor present in the skin, sweat, and other secretions which protects against Bb infection and opens an exciting therapeutic avenue for Lyme disease.

Abstract Background Congenital heart defects (CHD) are structural defects of the heart affecting approximately 1% of newborns. They exhibit low penetrance and non-Mendelian patterns of inheritance as varied and complex traits. While genetic factors are known to play an important role in the development of CHD, the specific genetics remain unknown for the majority of patients. To elucidate the underlying genetic risk, we performed a genome wide association study (GWAS) of CHDs in general and specific CHD subgroups using the FinnGen Release 10 (R10) (N > 393,000), followed by functional fine-mapping through eQTL and co-localization analyses using the GTEx database. Results We discovered three genome-wide significant loci associated with general CHD. Two of them were located in chromosome 17: 17q21.32 (rs2316327, intronic: LRRC37A2, Odds ratio (OR) [95% Confidence Interval (CI)] = 1.17[1.12–1.23], p = 1.5 × 10–9) and 17q25.3 (rs1293973611, nearest: BAHCC1, OR[95%CI] = 4.48[2.80–7.17], p = 7.0 × 10–10), respectively, and in addition to general CHD, the rs1293973611 locus was associated with the septal defect subtype. The third locus was in band 1p21.2 (rs35046143, nearest: PALMD, OR[95%CI] = 1.15[1.09–1.21], p = 7.1 × 10–9), and it was associated with general CHD and left-sided lesions. In the subgroup analysis, two additional loci were associated with septal defects (rs75230966 and rs6824295), and one with left-sided lesions (rs1305393195). In the eQTL analysis the variants rs2316327 (general CHD), and rs75230966 (septal defects) both located in 17q21.32 (with a LD r2 of 0.41) were both predicted to significantly associate with the expression of WNT9B in the atrial appendage tissue category. This effect was further confirmed by co-localization analysis, which also implicated WNT3 expression in the atrial appendage. A meta-analysis of general CHD together with the UK Biobank (combined N = 881,678) provided a different genome-wide significant locus in LRRC37A2; rs16941382 (OR[95%CI] = 1.15[1.11–1.20], p = 1.5 × 10–9) which is in significant LD with rs2316327. Conclusions Our results of general CHD and different CHD subcategories identified a complex risk locus on chromosome 17 near BAHCC1 and LRRC37A2, interacting with the genes WNT9B, WNT3 and MYL4, may constitute potential novel CHD risk associated loci, warranting future experimental tests to determine their role.

Abstract Nightmares are vivid, extended, and emotionally negative or negative dreams that awaken the dreamer. While sporadic nightmares and bad dreams are common and generally harmless, frequent nightmares often reflect underlying pathologies of emotional regulation. Indeed, insomnia, depression, anxiety, or alcohol use have been associated with nightmares in epidemiological and clinical studies. However, the connection between nightmares and their comorbidities are poorly understood. Our goal was to examine the genetic risk factors for nightmares and estimate correlation or causality between nightmares and comorbidities. We performed a genome-wide association study (GWAS) in 45,255 individuals using a questionnaire-based assessment on the frequency of nightmares during the past month and genome-wide genotyping data. While the GWAS did not reveal individual risk variants, heritability was estimated at 5%. In addition, the genetic correlation analysis showed a robust correlation (rg > 0.4) of nightmares with anxiety (rg = 0.671, p = 7.507e−06), depressive (rg = 0.562, p = 1.282e−07) and posttraumatic stress disorders (rg = 0.4083, p = 0.0152), and personality trait neuroticism (rg = 0.667, p = 4.516e−07). Furthermore, Mendelian randomization suggested causality from insomnia to nightmares (beta = 0.027, p = 0.0002). Our findings suggest that nightmares share genetic background with psychiatric traits and that insomnia may increase an individual’s liability to experience frequent nightmares. Given the significant correlations with psychiatric and psychological traits, it is essential to grow awareness of how nightmares affect health and disease and systematically collect information about nightmares, especially from clinical samples and larger cohorts.

Introduction Medication history errors at hospital admission are common and effective strategies to improve the quality of medication histories are still being researched. However, studies on new approaches regarding medication history taking are often time-consuming and resource-intensive. The gold standard when evaluating the quality of medication histories is the comparison of a Best Possible Medication History to the original. However, this double collection requires significant resources, disrupts clinical procedures, and places an additional burden on patients. Therefore, more efficient study designs need to be explored. We aimed to develop a design for future studies on medication history taking that uses fewer research resources and places less strain on patients and staff.Discussion We first identified shortcomings of the established study designs on medication history taking and subsequently defined requirements for a new design. A pragmatic study with an alternative endpoint was identified in a previous literature search. It served as the starting point from which we developed a new study design to assess the quality of approaches to medication history taking. Instead of taking a second medication history, a patient’s pre-existing medication document can be used as comparator to determine the quality of the medication history. Furthermore, we defined a new primary endpoint, i.e. the number of updates per patient. Updates are differences between the newly acquired medication history and the comparator. They include discontinued, initiated, and changed medications. To enhance our proposed design, we recommend a preparatory phase to identify a suitable comparator document, and a baseline phase to assess the current process.Conclusion We propose a more resource-efficient study design with a new endpoint. We plan to test its feasibility and evaluate whether it could enhance the efficacy of research on medication history taking in a pilot project.

Abstract Aquaculture is a key component of Ghana's food system strategies, promoting sustainable animal protein production. Aquaculture complements traditional marine capture fisheries to close the gap between demand and supply. However, about one third of fish produced globally have been reported to go to waste yearly. Among the various cultured fish, the Nile tilapia Oreochromis niloticus is a predominant species. This study aimed to estimate the extent of Nile tilapia wastage by consumers in Ghana. A web‐based cross‐sectional consumer survey was designed to assess the parts of the tilapia consumers generally classified as edible or inedible, taking into account the three primary tilapia preparation methods. The study utilised a semi‐structured online questionnaire, gathering responses from 246 participants. The parts of Nile tilapia investigated included the flesh, fins, offal, head, scales, bones, and gill flaps/opercula. The analysis of consumed and wasted parts of Nile tilapias by weight showed that, on average, the flesh made up the majority of the fish at 55.26%, followed by the head at 26.46%, offal at 8.51%, scales at 3.10%, fins at 2.93%, bones at 2.76%, and operculum at 0.98%, which was the smallest component. The study concluded that approximately 30%–45% of waste is generated from Nile tilapia in the Ghanaian supply chain. Tilapia was widely consumed by all groups, with an average liking score of 7.69 ± 1.95 on a 10‐point hedonic scale. A significant association was found between gender and consumption patterns with females showing a higher degree of liking. There was a strong association between the method of preparation and consumption patterns; the fried parts were classified as more edible compared to those that were boiled or grilled. To reduce waste in the aquaculture industry, tilapia and other fishes could be processed in a way that various edible and inedible parts are sold separately.

Abstract BackgroundEvent analysis is a promising approach to estimate the acceptance of medication alerts issued by computerized physician order entry (CPOE) systems with an integrated clinical decision support system (CDSS), particularly when alerts cannot be interactively confirmed in the CPOE-CDSS due to its system architecture. Medication documentation is then reviewed for documented evidence of alert acceptance, which can be a time-consuming process, especially when performed manually. ObjectiveWe present a new automated event analysis approach, which was applied to a large data set generated in a CPOE-CDSS with passive, noninterruptive alerts. MethodsMedication and alert data generated over 3.5 months within the CPOE-CDSS at Heidelberg University Hospital were divided into 24-hour time intervals in which the alert display was correlated with associated prescription changes. Alerts were considered “persistent” if they were displayed in every consecutive 24-hour time interval due to a respective active prescription until patient discharge and were considered “absent” if they were no longer displayed during continuous prescriptions in the subsequent interval. ResultsOverall, 1670 patient cases with 11,428 alerts were analyzed. Alerts were displayed for a median of 3 (IQR 1-7) consecutive 24-hour time intervals, with the shortest alerts displayed for drug-allergy interactions and the longest alerts displayed for potentially inappropriate medication for the elderly (PIM). Among the total 11,428 alerts, 56.1% (n=6413) became absent, most commonly among alerts for drug-drug interactions (1915/2366, 80.9%) and least commonly among PIM alerts (199/499, 39.9%). ConclusionsThis new approach to estimate alert acceptance based on event analysis can be flexibly adapted to the automated evaluation of passive, noninterruptive alerts. This enables large data sets of longitudinal patient cases to be processed, allows for the derivation of the ratios of persistent and absent alerts, and facilitates the comparison and prospective monitoring of these alerts.

Sairaaloiden lääkehoito on monimutkainen prosessi, johon liittyvistä virheistä saattaa potilaille aiheutuvien haittojen lisäksi koitua lisäkustannuksia terveydenhuoltojärjestelmälle. Suomessa on otettu enenevissä määrin käyttöön älylääkekaappeja, joiden yhtenä tavoitteena on vähentää lääkehoidon virheitä ja siten parantaa potilasturvallisuutta sekä sujuvoittaa henkilökunnan työskentelyä. Älylääkekaappien käyttöön on tunnistettu liittyvän käytännön haasteita, erityisesti sairaanhoitajien näkökulmasta. Käyttäjäkokemustutkimuksen tavoitteena oli selvittää, miten työprosesseja ja potilastietojärjestelmään integroitujen älylääkekaappien käyttöä voitaisiin kehittää vuodeosastoilla, jotta ammattilaisten työ sujuvoituisi potilasturvallisuutta vaarantamatta. Laadullinen tutkimusaineisto kerättiin keväällä 2023 haastattelemalla sairaanhoitajia (N=6), osastofarmaseutteja (N=3) ja lääketyöntekijöitä (N=2). Löydösten validoimiseksi ja kehitysehdotusten tuottamiseksi toteutettiin työpaja, johon osallistui noin 30 edustajaa eri ammattiryhmistä. Tutkimuksen tuloksena tunnistettiin seitsemän teemaa, joihin älylääkekaappien käyttöön liittyvät haasteet jakautuvat: työskentelyn keskeytyminen ja jonoutuminen, työprosessin hitaus, tilan puute, inhimilliset virheet ja osaamisen puute, tekniset haasteet, lääkkeiden jakoprosessista poikkeaminen sekä muut haasteita aiheuttavat älylääkekaapin ominaisuudet. Näiden pohjalta muodostettiin kehitysehdotuksia, jotka voidaan jakaa kolmeen teemaan: resurssit ja tilat, perehdytys ja ohjeistus sekä lääkkeiden säilytysratkaisut ja työprosessit. Jatkotutkimusta tarvitaan potilastietojärjestelmään integroitujen älylääkekaappien käyttäjäkokemuksista muilla vuodeosastoilla sekä mahdollisuuksista liittyen lääkkeiden annosjakeluun ja säilytykseen osittain myös älylääkekaappien ulkopuolella.

Introduction SARS-CoV-2 infection causes acute COVID-19 and may result in post-COVID syndrome (PCS). We aimed to investigate how clinicians diagnose PCS and identify associated clinical and demographic characteristics.Methods We analysed multiregistry data of all SARS-CoV-2 test-positive individuals in Sweden (n=1 057 174) between 1 February 2020 and 25 May 2021. We described clinical characteristics that prompt PCS diagnosis in outpatient and inpatient settings. In total, there were 6389 individuals with a hospital inpatient or outpatient diagnosis for PCS. To understand symptomatology, we examined individuals diagnosed with PCS at least 3 months after COVID-19 onset (n=6389) and assessed factors associated with PCS diagnosis.Results Mechanical ventilation correlated with PCS (OR 114.7, 95% CI 105.1 to 125.3) compared with no outpatient/inpatient contact during initial COVID-19. Dyspnoea (13.4%), malaise/fatigue (8%) and abnormal pulmonary diagnostic imaging findings (4.3%) were the most common features linked to PCS. We compared clinical features of PCS with matched controls (COVID-19 negative, n=23 795) and COVID-19 severity-matched patients (COVID-19 positive, n=25 556). Hypertension associated with PCS cohort (26.61%) than in COVID-19-negative (OR 17.16, 95% CI 15.23 to 19.3) and COVID-19-positive (OR 9.25, 95% CI 8.41 to 10.16) controls, although most individuals received this diagnosis before COVID-19. Dyspnoea was the second most common feature in the PCS cohort (17.2%), and new to the majority compared with COVID-19-negative (OR 54.16, 95% CI 42.86 to 68.45) and COVID-19-positive (OR 18.7, 95% CI 16.21 to 21.57) controls.Conclusions Our findings highlight factors Swedish physicians associate with PCS.

Quantitative systems pharmacology (QSP) models are rarely applied prospectively for decision-making in clinical practice. We therefore aimed to operationalize a QSP model for potas-sium homeostasis to predict potassium trajectories based on spironolactone administrations. For this purpose, we proposed a general workflow that was applied to electronic health records (EHR) from patients treated in a German tertiary care hospital. The workflow steps included model exploration, local and global sensitivity analyses (SA), identifiability analysis (IA) of model parameters, and specification of their inter-individual variability (IIV). Patient covariates, selected parameters, and IIV then defined prior information for the Bayesian a posteriori prediction of individual potassium trajectories of the following day. Following these steps, the successfully operationalized QSP model was interactively explored via a Shiny app. SA and IA yielded five influential and estimable parameters (extracellular fluid volume, hyperaldosteronism, mineral corticoid receptor abundance, potassium intake, sodium intake) for Bayesian prediction. The operationalized model was validated in nine pilot patients and showed satisfactory performance based on the (absolute) average fold error. This provides proof-of-principle for a Prescribing Monitoring of potassium concentrations in a hospital system, which could suggest preemptive clinical measures and therefore potentially avoid dangerous hyperkalemia or hypokalemia.

The objective of this study was to determine the daily dietary nicotinamide riboside (NR) dose required to maximize the delay of subjective muscle fatigue onset. Barrows (N = 100) were assigned to one of five treatments: a conventional swine finishing diet containing 0 (CON), 15 (15NR), 30 (30NR), 45 (45NR) mg·kg body weight−1·d−1 NR, or CON supplemented with 45 mg·kg body weight−1·d−1 NR by drench or cookie dough (DRE). All treatments were administered for the final 11 days of feeding. On supplementation d 10, barrows individually experienced a performance test at 1.09 m/s until they were subjectively exhausted. Wireless electromyography (EMG) sensors were affixed to the biceps femoris (BF), tensor fascia latae (TFL), and semitendinosus (ST) to measure real-time muscle activity. There were no treatment effects for barrow speed (p = 0.57), a tendency for a treatment effect (p = 0.07) for distance, and a treatment effect (p = 0.04) on time to exhaustion. Barrows of the 15NR and DRE treatments had greater (p = 0.05) distances to exhaustion than CON barrows but did not differ from other NR barrows (p > 0.11). Barrows in the 45NR treatment did not differ (p = 0.11) in distance from 30NR barrows but tended to have a greater (p = 0.07) distance compared to CON barrows. All other treatment comparisons did not differ (p > 0.27). Barrows in the DRE treatment moved for longer (p < 0.01) than CON barrows, but all other treatments did not differ from each other (p > 0.15). There was no treatment × period interaction for all muscles’ root mean square (RMS) values (p > 0.16), but there were Period effects for all muscles (p < 0.01) and a Treatment effect (p = 0.04) in the TFL. For all muscles, period 4 had greater RMS values than all other periods (p < 0.01), who did not differ from each other (p > 0.29). In the TFL, CON barrows had greater RMS values during the performance test compared to all NR treatments (p < 0.02), who did not differ from each other (p > 0.18). Overall, NR demonstrates potential in being a useful tool in fatigue prevention, but efficient administration of the compound needs further investigation.

Extracellular vesicles (EVs) are relatively recently discovered biological nanoparticles that mediate intercellular communication. The development of new methods for the isolation and characterization of EVs is crucial to support further studies on these small and structurally heterogenous vesicles. New scalable production methods are also needed to meet the needs of future therapeutic applications. A reliable inline detection method for the EV manufacturing process is needed to ensure reproducibility and to identify any possible variations in real time. Here, we demonstrate the use of an inline Raman detector in conjunction with anion exchange chromatography for the isolation of EVs from human platelets. Anion-exchange chromatography can be easily coupled with multiple inline detectors and provides an alternative to size-based methods for separating EVs from similar-sized impurities, such as lipoprotein particles. Raman spectroscopy enabled us to identify functional groups in EV samples and trace EVs and impurities in different stages of the process. Our results show a notable separation of impurities from the EVs during anion-exchange chromatography and demonstrate the power of inline Raman spectroscopy. Compared to conventional EV analysis methods, the inline Raman approach does not require hands-on work and can provide detailed, real-time information about the sample and the purification process.

Background/Objectives: Cystic fibrosis is a genetically determined disease that significantly influences and shortens life. Treatment with CFTR modulators (CFTR-T) is a new hope for patients. It can change the predictive values of a poor prognosis (e.g., exacerbation rate and FEV1 value). The aim of the study was to analyse exacerbation incidence and spirometry data before and after one year (+/− 2 weeks) of CFTR-T in 85 CF patients at the CF Centre in Poznań. To our knowledge, this is the first analysis of CFTR-T efficiency in the Central–Eastern Europe population. Methods: We retrospectively analysed the spirometry and exacerbation data of 85 CF adult patients (both men and women), who in the middle of 2022 began treatment with CFTR modulators. Results: The one-year ratio of hospitalisation caused by severe exacerbations lowered from 1.25 to 0.21 per patient per year. We also saw a 66% decline in ambulatory exacerbations. The median FEV1% increased by 9.60% in absolute values and by 460 mL. Even in the group with very severe obstruction (FEV1 < 35%), there was an increase in median FEV1% of 5.9 in absolute values. We also proved the increase in FVC% (median 17.10% in absolute value and 600 mL) in the study group. Conclusions: After one year of treatment, an impressive improvement was observed in two important predictive values of poor prognosis: exacerbation rate and FEV1 values. Further observation is needed to determine how long the improvement will be present and its influence on quality of life and life expectancy.

Objectives The objective of this study was to develop clinical classifiers aiming to identify prevalent ascending aortic dilatation in patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV).Design and setting A prospective, single-centre and observational cohort.Participants The study involved 543 BAV and 491 TAV patients with aortic valve disease and/or ascending aortic dilatation, excluding those with coronary artery disease, undergoing cardiothoracic surgery at the Karolinska University Hospital (Sweden).Main outcome measures Predictors of high risk of ascending aortic dilatation (defined as ascending aorta with a diameter above 40 mm) were identified through the application of machine learning algorithms and classic logistic regression models.Exposures Comprehensive multidimensional data, including valve morphology, clinical information, family history of cardiovascular diseases, prevalent diseases, demographic details, lifestyle factors, and medication.Results BAV patients, with an average age of 60.4±12.4 years, showed a higher frequency of aortic dilatation (45.3%) compared with TAV patients, who had an average age of 70.4±9.1 years (28.9% dilatation, p

Summary: Background: Anticipating the burden of intracerebral haemorrhage is crucial for proactive management and building resilience against future health challenges. Prior forecasts are based on population demography and to a lesser extent epidemiological trends. This study aims to utilise selected modifiable risk factors and socio-demographic indicators to forecast the incidence and mortality of intracerebral haemorrhage in Europe between 2019 and 2050. Methods: Three intracerebral haemorrhage risk factors identified in the Global Burden of Diseases, Injuries, and Risk Factors study (GBD 2019)—high systolic blood pressure, high fasting plasma glucose, and high body mass index—were utilised to predict the risk-attributable fractions between 2019 and 2050. Disease burden not attributable to these risk factors was then forecasted using time series models (autoregressive integrated moving average [ARIMA]), incorporating the Socio-demographic Index (SDI) as an external predictor. The optimal parameters of ARIMA models were selected for each age-sex-country group based on the Akaike Information Criterion (AIC). Different health scenarios were constructed by extending the past 85th and 15th percentiles of annualised rates of change in risk factors and SDI across all location-years, stratified by age and sex groups. A decomposition analysis was performed to assess the relative contributions of population size, age composition, and intracerebral haemorrhage risk on the projected changes. Findings: Compared with observed figures in 2019, our analysis predicts an increase in the burden of intracerebral haemorrhage in Europe in 2050, with a marginal rise of 0.6% (95% uncertainty interval [UI], −7.4% to 9.6%) in incident cases and an 8.9% (−2.8% to 23.6%) increase in mortality, reaching 141.2 (120.6–166.5) thousand and 144.2 (122.9–172.2) thousand respectively. These projections may fluctuate depending on trajectories of the risk factors and SDI; worsened trends could result in increases of 16.7% (8.7%–25.3%) in incidence and 31.2% (17.7%–48%) in mortality, while better trajectories may lead to a 10% (16.4%–2.3%) decrease in intracerebral haemorrhage cases with stabilised mortality. Individuals aged ≥80 years are expected to contribute significantly to the burden, comprising 62.7% of the cases in 2050, up from 40% in 2019, and 72.5% of deaths, up from 50.5%. Country-wide variations were noted in the projected changes, with decreases in the standardised rates across all nations but varying crude rates. The largest relative reductions in counts for both incidence and mortality are expected in Latvia, Bulgaria, and Hungary—ranging from −38.2% to −32.4% and −37.3% to −30.2% respectively. In contrast, the greatest increases for both measures were forecasted in Ireland (45.7% and 74.4%), Luxembourg (45% and 70.7%), and Cyprus (44.5% and 74.2%). The modelled increase in the burden of intracerebral haemorrhage could largely be attributed to population ageing. Interpretation: This study provides a comprehensive forecast of intracerebral haemorrhage in Europe until 2050, presenting different trajectories. The potential increase in the number of people experiencing and dying from intracerebral haemorrhage could have profound implications for both caregiving responsibilities and associated costs. However, forecasts were divergent between different scenarios and among EU countries, signalling the pivotal role of public health initiatives in steering the trajectories. Funding: The European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 754517. The National Institute for Health and Care Research (NIHR) under its Programme Grants for Applied Research (NIHR202339).

This paper analyses and compares the use of social media in school management in Ukraine and the United States. It examines the types of social media used, purposes for use, and challenges faced. Key findings show that Facebook, YouTube, Instagram and X are most popular in both countries. Social media communicates with stakeholders, showcases school activities, and builds relationships. Challenges include data privacy, digital literacy, and misinformation. The paper reviews training programs in both countries to improve social media competency for school leaders. It concludes that social media has become an essential communications tool in education, accelerated by the pandemic's impacts.

BackgroundEvidence for the beneficial effects of cognitive training on cognitive function and daily living activities is inconclusive. Variable study quality and design does not allow for robust comparisons/meta-analyses of different cognitive training programmes. Fairly low adherence to extended cognitive training interventions in clinical trials has been reported.AimsThe aim of further developing a Cognitive Training Support Programme (CTSP) is to supplement the Computerised Cognitive Training (CCT) intervention component of the multimodal Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), which is adapted to different cultural, regional and economic settings within the Word-Wide FINGERS (WW-FINGERS) Network. The main objectives are to improve adherence to cognitive training through a behaviour change framework and provide information about cognitive stimulation, social engagement and lifestyle risk factors for dementia.MethodsSix CTSP sessions were re-designed covering topics including (1) CCT instructions and tasks, (2) Cognitive domains: episodic memory, executive function and processing speed, (3) Successful ageing and compensatory strategies, (4) Cognitive stimulation and engagement, (5) Wellbeing factors affecting cognition (e.g., sleep and mood), (6) Sensory factors. Session content will be related to everyday life, with participant reflection and behaviour change techniques incorporated, e.g., strategies, goal-setting, active planning to enhance motivation, and adherence to the CCT and in relevant lifestyle changes.ConclusionsThrough interactive presentations promoting brain health, the programme provides for personal reflection that may enhance capability, opportunity and motivation for behaviour change. This will support adherence to the CCT within multidomain intervention trials. Efficacy of the programme will be evaluated through participant feedback and adherence metrics.

Introduction: Executive functions and processing speed have been regarded as core cognitive domains affected in cerebral small vessel disease (SVD). Executive functions, as an umbrella concept, consist of a variety of different subcomponents, yet in research these abilities are often evaluated with single tests or summary scores. Currently, it is unknown whether all executive abilities are equally affected by SVD brain changes and whether some tests are more sensitive in detecting deficits than others. We investigated the associations of white matter hyperintensity (WMH) volume with specific executive abilities (cognitive flexibility, response inhibition, working memory) and processing speed by using an extensive set of paper-and-pencil and computerised neuropsychological tests. Methods: In the Helsinki Small Vessel Disease Study, 152 subjects (age 65-75 years) with varying degrees of WMH but no clinical stroke or dementia were evaluated with quantitative automated MRI analysis and a comprehensive neuropsychological examination. Executive functions and processing speed measures included the Wechsler adult intelligence scale (WAIS-IV) Coding subtest, Stroop test, Hayling sentence completion test, Brixton spatial anticipation test, verbal fluency test, Wechsler memory scale (WMS-III) Digit span and Number-letter sequencing subtasks, and the more experimental Flexible attention test (FAT), Simon task and Sustained attention to response task (SART). Results: Linear regression analyses controlling for age, sex and education revealed significant associations between WMH volume and measures within all evaluated subdomains. However, marked differences were found between individual test Results: The strongest associations were observed for FAT Numbers and Number-letter task (computerised tests based on the Trail making test), FAT Visuospatial span, Simon task and verbal fluency (animals), while some of the widely used tests failed to reach significance. Discussion: WMH are related to significant deficits in processing speed and executive functions subdomains of flexibility, inhibition and working memory. The strength of associations within subdomains is nevertheless highly dependent on the evaluation method in use. Computerised tests providing precise measures of reaction times and response accuracy seem to outperform many of the conventional paper-and-pencil tests. These results have implications for observational studies and intervention trials, where the selection of sensitive outcome measures is crucial.

Introduction: Subjective cognitive complaints are common in patients with cerebral small vessel disease (SVD), yet their correspondence to informant evaluations, objective cognitive functions and severity of brain changes are poorly understood. We studied the associations of subjective and informant reports of cognitive difficulties (executive functions and memory) with findings from a comprehensive neuropsychological assessment and brain MRI (white matter hyperintensities, WMH volume) as well as depressive symptoms and functional abilities (instrumental activities of daily living, IADL). Methods: In the Helsinki SVD Study, 152 older adults with varying degrees of WMH but without stroke or dementia were classified as having normal cognition or mild cognitive impairment (MCI) based on Jak/Bondi neuropsychological criteria. The objective cognitive measures also included continuous domain scores for memory and executive functions. Cognitive complaints were evaluated with the subjective- and informant-versions of Prospective and Retrospective Memory Questionnaire (PRMQ) and Dysexecutive Questionnaire (DEX), functional abilities with the Amsterdam IADL Questionnaire and depressive symptoms with the Geriatric Depression Scale (GDS-15). Results: Subjective cognitive complaints correlated significantly with informant reports (r=0.40-0.50, p0.05). Instead, subjective DEX (OR 1.10, CI 95% 1.05-1.16, p

The knowledge that brain functional connectomes are unique and reliable has enabled behaviourally relevant inferences at a subject level. However, whether such “fingerprints” persist under altered states of consciousness is unknown. Ayahuasca is a potent serotonergic psychedelic which produces a widespread dysregulation of functional connectivity. Used communally in religious ceremonies, its shared use may highlight relevant novel interactions between mental state and functional connectome (FC) idiosyncrasy. Using 7T fMRI, we assessed resting-state static and dynamic FCs for 21 Santo Daime members after collective ayahuasca intake in an acute, within-subject study. Here, connectome fingerprinting revealed FCs showed reduced idiosyncrasy, accompanied by a spatiotemporal reallocation of keypoint edges. Importantly, we show that interindividual differences in higher-order FC motifs are relevant to experiential phenotypes, given that they can predict perceptual drug effects. Collectively, our findings offer an example of how individualised connectivity markers can be used to trace a subject's FC across altered states of consciousness.

Abstract Background Despite attempts to improve the cross-sectoral flow of information, difficulties remain in routine healthcare. The resulting negative impact on continuity of care is often associated with poor health outcomes, especially in older patients. Our intervention aims to increase information availability with respect to medications and health conditions at the interface between inpatient and outpatient care and to contribute towards improving the quality of care in older patients. This pilot study focuses on feasibility and implementability. Methods The idea of the complex intervention has been developed in a previous study. This intervention will be tested in a prospective, multicenter, cluster-randomized (via web tool), controlled pilot trial with two parallel study arms (intervention and control group). The pilot study will be conducted in 20 general practices in Hesse and Saxony (Germany) and include 200 patients (≥ 65 years of age with multimorbidity and polypharmacy) recruited by the practices. Practice staff and patients will be blinded. We will use qualitative and quantitative methods to assess the feasibility and implementability of the intervention and the study design in a process evaluation covering topics ranging from expectations to experiences. In addition, the feasibility of proposed outcome parameters for the future definitive trial will be explored. The composite endpoint will include health-related patient outcomes (hospitalization, falls, and mortality using, e.g., the FIMA questionnaire), and we will assess information on medications (SIMS questionnaire), symptoms and side effects of the medication (pro-CTCAE questionnaire), and health literacy (HLQ questionnaire). Data will be collected at study begin (baseline) and after 6 months. Furthermore, the study will include surveys and interviews with patients, general practitioners, and healthcare assistants. Discussion The intervention was developed using a participatory approach involving stakeholders and patients. It aims to empower general practice teams as they provide patient-centered care and play a key role in the coordination and continuity of care. We aim to encourage patients to adopt an active role in their health care. Overall, we want to increase the availability of health-related information for patients and healthcare providers. The results of the pilot study will be used in the design and implementation of the future definitive trial. Trial registration The study was registered in DRKS-German Clinical Trials Register: registration number DRKS00027649 (date: 19 January 2022). Date and version identifier 10.07.2023; Version 1.3

Abstract Gutta percha, natural rubber, and balata are latexes produced by tropical trees that since the mid-nineteenth century have been extensively used commercially and in the creation of artworks and daily use objects. All three latexes are stereoisomers of polyisoprene that differ in their molecular structure. In gutta percha and balata, the molecular functional group is in the trans- position; in natural rubber, it is in the cis- position. This difference in their molecular structure affects the physical properties of these materials and their aging, turning natural rubber tacky and gutta percha brittle. Commercially focused analysis of natural polyisoprenes has typically used chemically modified materials. The present study characterizes natural, chemically unadulterated latex harvested from trees, aiming to differentiate the cis- and trans-forms. The analysed materials comprised fresh latexes harvested in Malaysia and Indonesia, naturally aged botanical samples, some over 100 years old, and minimally processed 10-year-old commercial stock; a total of 50 samples were examined, out of which 23 are discussed in detail. The harvesting practices of latexes were recorded during fieldwork in Southeast Asia in 2015–2019, in Cipetir (Tjipetir), on Lingga Island in Indonesia, and in Malay rubber plantations. The harvesting methods are the first indicators as to the type of latex harvested based on the pattern of incisions and time of coagulation upon exposure to air. The interviews of tappers, especially of gutta percha and balata, serve as a record of a disappearing craft. Therefore, this fieldwork report contributing to a general knowledge of working methods with natural latexes is of particular value considering the scarcity of published records. The laboratory analytical study of trans- and cis- forms relied on nuclear magnetic resonance (NMR) spectroscopy, which is the most accurate method to unambiguously determine the stereo chemistry of each polyisoprene. The characteristic spectroscopic features of cis- and trans-positions were clearly shown in all samples, in fresh latex, in over 100-year-old material, and in early twentieth century artifacts. This result indicated that the aging of the polyisoprenes does not prevent the identification of their stereochemistry. This analytical work is the first thorough examination of gutta percha, natural rubber and balata in the context of cultural heritage to guide preservation strategies for objects made of these materials.

Abstract Background Stochastic optical reconstruction microscopy (STORM), a super-resolution microscopy technique based on single-molecule localizations, has become popular to characterize sub-diffraction limit targets. However, due to lengthy image acquisition, STORM recordings are prone to sample drift. Existing cross-correlation or fiducial marker-based algorithms allow correcting the drift within each channel, but misalignment between channels remains due to interchannel drift accumulating during sequential channel acquisition. This is a major drawback in multi-color STORM, a technique of utmost importance for the characterization of various biological interactions. Results We developed RegiSTORM, a software for reducing channel misalignment by accurately registering STORM channels utilizing fiducial markers in the sample. RegiSTORM identifies fiducials from the STORM localization data based on their non-blinking nature and uses them as landmarks for channel registration. We first demonstrated accurate registration on recordings of fiducials only, as evidenced by significantly reduced target registration error with all the tested channel combinations. Next, we validated the performance in a more practically relevant setup on cells multi-stained for tubulin. Finally, we showed that RegiSTORM successfully registers two-color STORM recordings of cargo-loaded lipid nanoparticles without fiducials, demonstrating the broader applicability of this software. Conclusions The developed RegiSTORM software was demonstrated to be able to accurately register multiple STORM channels and is freely available as open-source (MIT license) at https://github.com/oystein676/RegiSTORM.git and https://doi.org/10.5281/zenodo.5509861 (archived), and runs as a standalone executable (Windows) or via Python (Mac OS, Linux).

Abstract Artificial intelligence methods including deep neural networks (DNN) can provide rapid molecular classification of tumors from routine histology with accuracy that matches or exceeds human pathologists. Discerning how neural networks make their predictions remains a significant challenge, but explainability tools help provide insights into what models have learned when corresponding histologic features are poorly defined. Here, we present a method for improving explainability of DNN models using synthetic histology generated by a conditional generative adversarial network (cGAN). We show that cGANs generate high-quality synthetic histology images that can be leveraged for explaining DNN models trained to classify molecularly-subtyped tumors, exposing histologic features associated with molecular state. Fine-tuning synthetic histology through class and layer blending illustrates nuanced morphologic differences between tumor subtypes. Finally, we demonstrate the use of synthetic histology for augmenting pathologist-in-training education, showing that these intuitive visualizations can reinforce and improve understanding of histologic manifestations of tumor biology.

Abstract Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

Abstract Background Malnutrition (i.e., protein-energy malnutrition) in older adults has severe negative clinical consequences, emphasizing the need for effective treatments. Many, often small, randomized controlled trials (RCTs) testing the effectiveness of nutritional interventions for the treatment of malnutrition showed mixed results and a need for meta-analyses and data pooling has been expressed. However, evidence synthesis is hampered by the wide variety of outcomes and their method of assessment in previous RCTs. This paper describes the protocol for developing a Core Outcome Set (COS) for nutritional intervention studies in older adults with malnutrition and those at risk. Methods The project consists of five phases. The first phase consists of a scoping review to identify frequently used outcomes in published RCTs and select additional patient-reported outcomes. The second phase includes a modified Delphi Survey involving experienced researchers and health care professionals working in the field of malnutrition in older adults, followed by the third phase consisting of a consensus meeting to discuss and agree what critical outcomes need to be included in the COS. The fourth phase will determine how each COS outcome should be measured based on a systematic literature review and a second consensus meeting. This will be followed by a dissemination and implementation phase. Patient and Public Involvement (PPI) representatives will contribute to study design, oversight, consensus, and dissemination. Conclusions The result of this project is a COS that should be included in any RCT evaluating the effect of nutritional interventions in older adults with malnutrition and those at risk. This COS will facilitate comparison of RCT results, will increase efficient use of research resources and will reduce bias due to measurement of the outcome and publication bias. Ultimately, the COS will support clinical decision making by identifying the most effective approaches for treating and preventing malnutrition in older adults.

Background Excessive daytime sleepiness (EDS), experienced in 10% to 20% of the population, has been associated with cardiovascular disease and death. However, the condition is heterogeneous and is prevalent in individuals having short and long sleep duration. We sought to clarify the relationship between sleep duration subtypes of EDS with cardiovascular outcomes, accounting for these subtypes. Methods and Results We defined 3 sleep duration subtypes of excessive daytime sleepiness: normal (6–9 hours), short (9 hours), and compared these with a nonsleepy, normal‐sleep‐duration reference group. We analyzed their associations with incident myocardial infarction (MI) and stroke using medical records of 355 901 UK Biobank participants and performed 2‐sample Mendelian randomization for each outcome. Compared with healthy sleep, long‐sleep EDS was associated with an 83% increased rate of MI (hazard ratio, 1.83 [95% CI, 1.21–2.77]) during 8.2‐year median follow‐up, adjusting for multiple health and sociodemographic factors. Mendelian randomization analysis provided supporting evidence of a causal role for a genetic long‐sleep EDS subtype in MI (inverse‐variance weighted β=1.995, P=0.001). In contrast, we did not find evidence that other subtypes of EDS were associated with incident MI or any associations with stroke (P>0.05). Conclusions Our study suggests the previous evidence linking EDS with increased cardiovascular disease risk may be primarily driven by the effect of its long‐sleep subtype on higher risk of MI. Underlying mechanisms remain to be investigated but may involve sleep irregularity and circadian disruption, suggesting a need for novel interventions in this population.

Summary: Background: Preeclampsia has been associated with maternal epigenetic changes, in particular DNA methylation changes in the placenta. It has been suggested that preeclampsia could also cause DNA methylation changes in the neonate. We examined DNA methylation in relation to gene expression in the cord blood of offspring born to mothers with preeclampsia. Methods: This study included 128 mother-child pairs who participated in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), where assessment of preeclampsia served as secondary outcome. We performed an epigenome-wide association study of preeclampsia and cord blood DNA methylation (Illumina 450 K chip). We then examined gene expression of the same subjects for validation and replicated the gene signatures in independent DNA methylation datasets. Lastly, we applied functional enrichment and network analyses to identify biological pathways that could potentially be involved in preeclampsia. Findings: In the cord blood samples (n = 128), 263 CpGs were differentially methylated (FDR

Martin Lund,1,&ast; Ditte Valsgaard Vammen,2,&ast; Milad Hanna,3 Søren Høyer,4 Lars Lund1,2,5 1Department of Urology, Odense University Hospital, Odense, Denmark; 2Department of Urology, Viborg Hospital, Viborg, Denmark; 3Department of Urology, Imperial College National Health Service Trust, London, UK; 4Department of Pathology, Aarhus University Hospital, Aarhus, Denmark; 5Clinical Institute, University of Southern Denmark, Odense, Denmark&ast;These authors contributed equally to this workCorrespondence: Lars Lund, Department of Urology, Odense University Hospital, Sdr. Boulevard 29, Odense, DK-5000, Denmark, Tel +45 5140 8982, Fax +45 6541 1726, Email Lars.Lund@rsyd.dkObjective: Low-energy extracorporeal shockwave therapy (LE-ESWT) has been shown to induce organ repair and neo-vascularization. The ability of LE-ESWT to improve erectile function in rodents as measured by improvements in intracavernosal pressure is well-established in various pathological situations. The underlying molecular mechanism are unclear and likely vary between different disorders, making rational drug design for synergetic effects with LE-ESWT difficult, without further research. In this placebo-controlled study, we aim to establish whether LE-ESWT can activate neovascularization biomarkers in diabetic tissues.Material and Methods: Forty Wistar rats, aged 8 weeks, were randomly divided into 4 groups: 8 untreated controls, 12 controls that underwent LE-ESWT treatment, 8 controls with induced diabetes mellitus (DM) and 12 with DM underwent LE-ESWT treatment. DM was induced by streptozotocin. LE-ESWT treatment was performed with a Duolith SD1 machine (Storz), with a total amount of energy of 6.4 J per treatment. The rats received a total of three LE-ESWT treatments with 2-week intervals between treatments.Results: Diabetic rats had significantly elevated blood glucose concentrations compared to control rats (P < 0.001) and experienced significant weight loss compared to controls (P < 0.001). Diabetic rats had elevated creatinine and urea and lower albumin (P < 0.001). Histologic analysis of penile tissue showed significant levels of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) expression in the LE-ESWT groups compared to controls (P< 0.01).Conclusion: LE-ESWT induces neo-angiogenesis as expressed by VEGF and FGF in erectile tissue in normal and diabetic rats.Keywords: erectile dysfunction, diabetes mellitus, extracorporeal shockwave therapy

This study reports a dense, late summer phytoplankton bloom in the Southern Ocean that accumulated unusually high levels of organic matter and supported feeding hot spots for birds and whales. The authors show that this recurring open ocean bloom is driven by anomalies in easterly winds that push sea ice southwards and favour the upwelling of deep waters enriched in hydrothermal iron.

Abstract Background In mammals, the gut microbiota has important effects on the health of their hosts. Recent research highlights that animal populations that live in captivity often differ in microbiota diversity and composition from wild populations. However, the changes that may occur when animals move to captivity remain difficult to predict and factors generating such differences are poorly understood. Here we compare the bacterial gut microbiota of wild and captive Damaraland mole-rats (Fukomys damarensis) originating from a population in the southern Kalahari Desert to characterise the changes of the gut microbiota that occur from one generation to the next generation in a long-lived, social rodent species. Results We found a clear divergence in the composition of the gut microbiota of captive and wild Damaraland mole-rats. Although the dominating higher-rank bacterial taxa were the same in the two groups, captive animals had an increased ratio of relative abundance of Firmicutes to Bacteroidetes compared to wild animals. The Amplicon Sequence Variants (ASVs) that were strongly associated with wild animals were commonly members of the same bacterial families as those strongly associated with captive animals. Captive animals had much higher ASV richness compared to wild-caught animals, explained by an increased richness within the Firmicutes. Conclusion We found that the gut microbiota of captive hosts differs substantially from the gut microbiota composition of wild hosts. The largest differences between the two groups were found in shifts in relative abundances and diversity of Firmicutes and Bacteroidetes.

Gastrointestinal neoplasms most commonly metastasize to the liver, where they are typically found as solid and hypervascular lesions. Here, we describe a case of a 44-year-old man with a leiomyosarcoma of the rectum, who at the time of diagnosis presented with a small (5 mm in diameter) cyst-like lesion in the liver. Positron emission tomography demonstrated no increased metabolism in the area of the cyst, suggesting a benign character of the lesion. However, after 3 years, CT scans revealed enlargement of the cyst, and local surgical excision was performed. The results of histopathological examination of the resected material were consistent with metastatic leiomyosarcoma. Subsequently, the patient developed lung metastases and died within 2 years. Our case describes a very rare presentation of leiomyosarcoma’s metastasis that led to an ill-fated misdiagnosis and dismal disease outcome.

Abstract Background High-dose chemotherapy with autologous stem cell rescue (HDCT) is a promising treatment for patients with stage III, HER2-negative, homologous recombination deficient (HRD) breast cancer. Clinical effectiveness and cost-effectiveness are currently under investigation in an international multicenter randomized controlled trial. To increase the chance of successful introduction of HDCT into daily clinical practice, we aimed to identify relevant factors for smooth implementation using an early comprehensive assessment framework. Methods This is a qualitative, multi-stakeholder, exploratory research using semi-structured interviews guided by the Constructive Technology Assessment model, which evaluates the quality of a novel health technology by clinical, economic, patient-related, and organizational factors. Stakeholders were recruited by purposeful stratified sampling and interviewed until sufficient content saturation was reached. Two researchers independently created themes, categories, and subcategories by following inductive coding steps, these were verified by a third researcher. Results We interviewed 28 stakeholders between June 2019 and April 2021. In total, five overarching themes and seventeen categories were identified. Important findings for optimal implementation included the structural identification and referral of all eligible patients, early integration of supportive care, multidisciplinary collaboration between- and within hospitals, (de)centralization of treatment aspects, the provision of information for patients and healthcare professionals, and compliance to new regulation for the BRCA1-like test. Conclusions In anticipation of a positive reimbursement decision, we recommend to take the highlighted implementation factors into consideration. This might expedite and guide high-quality equitable access to HDCT for patients with stage III, HER2-negative, HRD breast cancer in the Netherlands.

ObjectiveDuring the first wave of the COVID-19 pandemic in 2020, non-essential health services were suspended in Belgium, and the public was ordered to socially isolate. Underdiagnosis of cancer during this period was reported worldwide. Certain risk factors for head and neck cancer (HNC) overlap with those for COVID-19 incidence and mortality, making underdiagnosis and subsequent stage shift of this potentially rapidly progressing cancer a major concern. We aimed to analyze incidence, clinical stage at presentation, and survival of patients diagnosed with HNC in 2020 in Belgium, considering recent temporal trends.MethodsUsing population-based data from the Belgian Cancer Registry (BCR), we extrapolated 2017-2019 trends in incidence, clinical stage, and 1-year relative survival (1yRS) of HNC to create an expected value for 2020 and compared this to the observed value.ResultsThere were 9.5% fewer HNCs diagnosed in 2020, compared to the predicted incidence. Underdiagnosis was larger for males (-11.8%), patients aged 50-64 (-11.2%) and 65-79 (-11.1%), and for oral cavity cancer (-17.6%). Shifts to more advanced stages were observed in larynx and oropharynx tumors and for (male) patients aged 80+. A 2.4 percentage point decline in 1yRS was observed, relative to the increasing trends in 1yRS (2017-2019).ConclusionThe COVID-19 pandemic led to underdiagnosis of HNC, resulting in shifts to more advanced stage at presentation in certain subgroups. A stage shift can be expected for the 9.5% of tumors not yet diagnosed at the end of 2020. HNC patients diagnosed in 2020 suffered higher than expected mortality.

Polygenic risk scores (PRSs) estimate genetic liability for diseases and traits. However, the portability of PRSs in sleep traits has remained elusive. We generated PRSs for self-reported insomnia, chronotype and sleep duration using summary data from genome-wide association studies (GWASs) performed in 350,000 to 697,000 European-ancestry individuals. We then projected the scores in two independent Finnish population cohorts (N = 33,493) and tested whether the PRSs were associated with their respective sleep traits. We observed that all the generated PRSs were associated with their corresponding traits (p < 0.05 in all cases). Furthermore, we found that there was a 22.2 min difference in reported sleep between the 5% tails of the PRS for sleep duration (p < 0.001). Our findings indicate that sleep-related PRSs show portability across cohorts. The findings also demonstrate that sleep measures using PRSs for sleep behaviors may provide useful instruments for testing disease and trait associations in cohorts where direct sleep parameters have not yet been measured.

Abstract Background Pharmacist-led medication review and medication management programs (MMP) are well-known strategies to improve medication safety and effectiveness. If performed interprofessionally, outcomes might even improve. However, little is known about task sharing in interprofessional MMP, in which general practitioners (GPs) and community pharmacists (CPs) collaboratively perform medication reviews and continuously follow-up on patients with designated medical and pharmaceutical tasks, respectively. In 2016, ARMIN (Arzneimittelinitiative Sachsen-Thüringen) an interprofessional MMP was launched in two German federal states, Saxony and Thuringia. The aim of this study was to understand how GPs and CPs share tasks in MMP when reviewing the patients’ medication. Methods This was a cross-sectional postal survey among GPs and CPs who participated in the MMP. Participants were asked who completed which MMP tasks, e.g., checking drug-drug interactions, dosing, and side effects. In total, 15 MMP tasks were surveyed using a 5-point Likert scale ranging from “I complete this task alone” to “GP/CP completes this task alone”. The study was conducted between 11/2020 and 04/2021. Data was analyzed using descriptive statistics. Results In total, 114/165 (69.1%) GPs and 166/243 (68.3%) CPs returned a questionnaire. The majority of GPs and CPs reported (i) checking clinical parameters and medication overuse and underuse to be completed by GPs, (ii) checking storage conditions of drugs and initial compilation of the patient’s medication including brown bag review being mostly performed by CPs, and (iii) checking side-effects, non-adherence, and continuous updating of the medication list were carried out jointly. The responses differed most for problems with self-medication and adding and removing over-the-counter medicines from the medication list. In addition, the responses revealed that some MMP tasks were not sufficiently performed by either GPs or CPs. Conclusions Both GPs’ and CPs’ expertise are needed to perform MMP as comprehensively as possible. Future studies should explore how GPs and CPs can complement each other in MMP most efficiently.

We have recently demonstrated that fibroblast growth factor receptor 2 (FGFR2)‐mediated signalling alters progesterone receptor (PR) activity and response of oestrogen receptor α (ER)‐positive (ER+) breast cancer (BCa) cell lines to anti‐ER agents. Little is known about whether the crosstalk between ER and PR, shown to be modulated by the hormonal background, might also be affected by FGFR2. Here, PR‐dependent behaviour of ER+ BCa cells was studied in the presence of oestrogen (E2) and progesterone (P4) and/or FGF7. In vitro analyses showed that FGF7/FGFR2 signalling: (a) abolished the effect of P4 on E2‐promoted 3D cell growth and response to tamoxifen; (b) regulated ER and PR expression and activity; (c) increased formation of ER–PR complexes; and (d) reversed P4‐triggered deregulation of ER‐dependent genes. Analysis of clinical data demonstrated that the prognostic value of FGFR2 varied between patients with different menopausal status; that is, high expression of FGFR2 was significantly associated with longer progression‐free survival (PFS) in postmenopausal patients, whereas there was no significant association in premenopausal patients. FGFR2 was found to positively correlate with the expression of JunB proto‐oncogene, AP‐1 transcription factor subunit (JUNB), an ER‐dependent gene, only in premenopausal patients. Molecular analyses revealed that the presence of JunB was a prerequisite for FGFR2‐mediated abrogation of P4‐induced inhibition of cell growth. Our results demonstrate for the first time that the FGF7/FGFR2–JunB axis abolishes the modulatory effects of PR on ER‐associated biological functions in premenopausal ER+ BCa. This may provide foundations for a better selection of patients for FGFR‐targeting therapeutic strategies.

Abstract Background Flavonols are the largest subgroup of flavonoids, possessing multiple functions in plants including protection against ultraviolet radiation, antimicrobial activities, and flower pigmentation together with anthocyanins. They are of agronomical and economical importance because the major off-taste component in rapeseed protein isolates is a flavonol derivative, which limits rapeseed protein use for human consumption. Flavonol production in Arabidopsis thaliana is mainly regulated by the subgroup 7 (SG7) R2R3-MYB transcription factors MYB11, MYB12, and MYB111. Recently, the SG19 MYBs MYB21, MYB24, and MYB57 were shown to regulate flavonol accumulation in pollen and stamens. The members of each subgroup are closely related, showing gene redundancy and tissue-specific expression in A. thaliana. However, the evolution of these flavonol regulators inside the Brassicaceae, especially inside the Brassiceae, which include the rapeseed crop species, is not fully understood. Results We studied the SG7 and SG19 MYBs in 44 species, including 31 species of the Brassicaceae, by phylogenetic analyses followed by synteny and gene expression analyses. Thereby we identified a deep MYB12 and MYB111 duplication inside the Brassicaceae, which likely occurred before the divergence of Brassiceae and Thelypodieae. These duplications of SG7 members were followed by the loss of MYB11 after the divergence of Eruca vesicaria from the remaining Brassiceae species. Similarly, MYB21 experienced duplication before the emergence of the Brassiceae tribe, where the gene loss of MYB24 is also proposed to have happened. The members of each subgroup revealed frequent overlapping spatio-temporal expression patterns in the Brassiceae member B. napus, which are assumed to compensate for the loss of MYB11 and MYB24 in the analysed tissues. Conclusions We identified a duplication of MYB12, MYB111, and MYB21 inside the Brassicaceae and MYB11 and MYB24 gene loss inside the tribe Brassiceae. We propose that polyploidization events have shaped the evolution of the flavonol regulators in the Brassicaceae, especially in the Brassiceae.

Abstract Background Symptoms of depression and anxiety are elevated among parents of children with cancer. However, knowledge of parents' psychotropic medication use following child's cancer diagnosis is scarce. Methods We use longitudinal Finnish register data on 3266 mothers and 2687 fathers whose child (aged 0–19) was diagnosed with cancer during 2000–2016. We record mothers' and fathers' psychotropic medication use (at least one annual purchase of anxiolytics, hypnotics, sedatives, or antidepressants) 5 years before and after the child's diagnosis and assess within‐individual changes in medication use by time since diagnosis, cancer type, child's age, presence of siblings, and parent's living arrangements and education using linear probability models with the individual fixed‐effects estimator. The fixed‐effects models compare each parent's annual probability of psychotropic medication use after diagnosis to their annual probability of medication use during the 5‐year period before the diagnosis. Results Psychotropic medication use was more common among mothers than fathers already before the child's diagnosis, 11.2% versus 7.3%. Immediately after diagnosis, psychotropic medication use increased by 6.0 (95% CI 4.8–7.2) percentage points among mothers and by 3.2 (CI 2.1–4.2) percentage points among fathers. Among fathers, medication use returned to pre‐diagnosis level by the second year, except among those whose child was diagnosed with acute lymphoblastic leukemia or lymphoblastic lymphoma. Among mothers of children with a central nervous system cancer, medication use remained persistently elevated during the 5‐year follow‐up. For mothers with other under‐aged children or whose diagnosed child was younger than 10 years, the return to pre‐diagnosis level was also slow. Conclusions Having a child with cancer clearly increases parents' psychotropic medication use. The increase is smaller and more short‐lived among fathers, but among mothers its duration depends on both cancer type and family characteristics. Our results suggest that an increased care burden poses particular strain to the long‐term mental well‐being of mothers.