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Global health champions modernism and biomedical knowledge but tends to neglect knowledge, beliefs and identities of rural communities in low-income and middle-income countries. The topic of antimicrobial resistance represents these common challenges, wherein the growing emphasis on public engagement offers a yet underdeveloped opportunity to generate perspectives and forms of knowledge that are not typically incorporated into research and policy. The medical humanities as an interdisciplinary approach to illness and health behaviour play a central role in cultivating this potential-in particular, through the field's emphasis on phenomenological and intersubjective approaches to knowledge generation and its interest in dialogue between medicine, the humanities and the broader public.We present a case study of public engagement that incorporates three medical humanities methods: participatory co-production, photographic storytelling and dialogue between researchers and the public. Situated in the context of northern Thailand, we explore subcases on co-production workshops with villagers, tales of treatment shared by traditional healers and dialogue surrounding artistic display in an international photo exhibition. Our starting assumption for the case study analysis was that co-produced local inputs can (and should) broaden the understanding of the sociocultural context of antimicrobial resistance.Our case study illustrates the potential of medical humanities methods in public engagement to foreground cultural knowledge, personal experience and 'lay' sensemaking surrounding health systems and healing (including medicine use). Among others, the engagement activities enabled us to formulate and test locally grounded hypotheses, gain new insights into the social configuration of treatment seeking and reflect on the relationship between traditional healing and modern medicine in the context of antimicrobial resistance. We conclude that medical-humanities-informed forms of public engagement should become a standard component of global health research, but they require extensive evaluation to assess benefits and risks comprehensively., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Abstract In baseball pitchers the elbow is exposed to high and repetitive loads (i.e. external valgus torque), caused by pitching a high number of balls in a practice session or game. This can result in overuse injuries like the ulnar collateral ligament (UCL) injury. To understand injury mechanisms, the effect of repetitive pitching on the elbow load magnitude and variability was investigated. In addition, we explored whether repetitive pitching affects elbow muscle activation during pitching. Fifteen pitchers threw each 60 to 110 balls. The external valgus torque and electromyography of three elbow muscles were quantified during each pitch. Linear mixed model analyses were performed to investigate the effect of repetitive pitching. On a group level, the linear mixed models showed no significant associations of repetitive pitching with valgus torque magnitude and variability and elbow muscle activity. Significant differences exist between pitchers in their individual trajectories in elbow valgus torque and muscle activity with repetitive pitching. This shows the importance of individuality in relation to repetitive pitching. In order to achieve effective elbow injury prevention in baseball pitching, individual characteristics of changes in elbow load and muscle activity in relation to the development of UCL injuries should be investigated.

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental condition with onset in early childhood, still diagnosed only through clinical observation due to the lack of laboratory biomarkers. Early detection strategies would be especially useful in screening high-risk newborn siblings of children already diagnosed with ASD. We performed RNA sequencing on peripheral blood, comparing 27 pairs of ASD children vs their sex- and age-matched unaffected siblings. Differential gene expression profiling, performed applying an unpaired model found two immune genes, EGR1 and IGKV3D-15, significantly upregulated in ASD patients (both p adj = 0.037). Weighted gene correlation network analysis identified 18 co-expressed modules. One of these modules was downregulated among autistic individuals (p = 0.035) and a ROC curve using its eigengene values yielded an AUC of 0.62. Genes in this module are primarily involved in transcriptional control and its hub gene, RACK1, encodes for a signaling protein critical for neurodevelopment and innate immunity, whose expression is influenced by various hormones and known "endocrine disruptors". These results indicate that transcriptomic biomarkers can contribute to the sensitivity of an intra-familial multimarker panel for ASD and provide further evidence that neurodevelopment, innate immunity and transcriptional regulation are key to ASD pathogenesis.

Introduction Acute mesenteric ischaemia (AMI) is a life-threatening condition with short-term mortality of up to 80%. The diagnosis of AMI has remained troublesome due to the non-specific clinical presentation, symptoms and laboratory findings. Early unambiguous diagnosis of AMI is critical to prevent progression from reversible to irreversible transmural intestinal damage, thereby decreasing morbidity and improving survival. The present study aims to validate a panel of plasma biomarkers and investigate volatile organic compound (VOC) profiles in exhaled air as a tool to timely and accurately diagnose AMI.Methods and analysis In this international multicentre prospective observational study, 120 patients (>18 years of age) will be recruited with clinical suspicion of AMI. Clinical suspicion is based on: (1) clinical manifestation, (2) physical examination, (3) laboratory measurements and (4) the physician’s consideration to perform a CT scan. The patient’s characteristics, repetitive blood samples and exhaled air will be prospectively collected. Plasma levels of mucosal damage markers intestinal fatty acid-binding protein and villin-1, as well as transmural damage marker smooth muscle protein 22-alpha, will be assessed by ELISA. Analysis of VOCs in exhaled air will be performed by gas chromatography time-of-flight mass spectrometry. Diagnosis of AMI will be based on CT, endovascular and surgical reports, clinical findings, and (if applicable) verified by histopathological examination.Ethics and dissemination The study protocol was approved by the Medical Research Ethics Committee (METC) of Maastricht University Medical Centre+ and Maastricht University (METC azM/UM), the Netherlands (METC19-010) and the Ethics Committee Research UZ/KU Leuven, Belgium (S63500). Executive boards and local METCs of other Dutch participating centres Gelre Ziekenhuizen (Apeldoorn), Medisch Spectrum Twente (Enschede), and University Medical Centre Groningen have granted permission to carry out this study. Study results will be disseminated via open-access peer-reviewed scientific journals and national/international conferences.Trial registration number NCT05194527.

Objective Surgical denervation has been proposed as a treatment for pain in hand osteoarthritis (OA). This review aimed to summarise the available evidence and to propose a research agenda.Methods A systematic literature search was performed up to September 2022. Two investigators independently identified studies that reported on denervation for OA of the proximal interphalangeal, distal interphalangeal, metacarpophalangeal or carpometacarpal joints. Quality of studies was assessed and study characteristics, patient characteristics, details of the surgical technique and outcomes of the surgery were extracted.Results Of 169 references, 17 articles reporting on 384 denervations in 351 patients were selected. Sixteen case series reported positive outcomes with respect to pain, function and patient satisfaction. One non-randomised clinical trial reported no difference in outcome when comparing denervation of the first carpometacarpal (CMC I) joint to trapeziectomy. Adverse events were frequent, with sensory abnormalities occurring the most, followed by the need for revision surgery. All studies had significant risk of bias.Conclusion Surgical denervation for pain in hand OA shows some promise, but the available evidence does not allow any conclusions of efficacy and higher-quality research is needed. Techniques should be harmonised and more data regarding how denervation compares to current usual care, other denervation methods or placebo in terms of outcomes and adverse events are needed.

Severe infections with potentially fatal outcomes are caused by parasites from the genera Trypanosoma and Leishmania (class Kinetoplastea). The diseases affect people of remote areas in the tropics and subtropics with limited access to adequate health care. Besides insufficient diagnostics, treatment options are limited, with tenuous developments in recent years. Therefore, new antitrypanosomal antiinfectives are required to fight these maladies. In the presented approach, new compounds were developed and tested on the target trypanothione synthetase (TryS). This enzyme is crucial to the kinetoplastids' unique trypanothione-based thiol redox metabolism and thus for pathogen survival. Preceding studies have shown that N5-substituted paullones display antitrypanosomal activity as well as TryS inhibition. Herein, this compound class was further examined regarding the structure-activity relationships (SAR). Diverse benzazepinone derivatives were designed and tested in cell-based assays on bloodstream Trypanosoma brucei brucei (T. b. brucei) and intracellular amastigotes of Leishmania infantum (L. infantum) as well as in enzyme-based assays on L. infantum TryS (LiTryS) and T. b. brucei TryS (TbTryS). While an exchange of just the substituent in the 9-position of paullones led to potent inhibitors on LiTryS and T. b. brucei parasites, new compounds lacking the indole moiety showed a total loss of activity in both assays. Conclusively, the indole as part of the paullone structure is pivotal for keeping the TryS inhibitory and antitrypanosomal activity of this substance class.

ObjectiveTimely identification of patients who carry multidrug-resistant microorganisms (MDRO) is needed to prevent nosocomial spread to other patients and to the hospital environment. We aimed to compare the yield of a universal screening strategy upon admission to the currently installed universal risk assessment combined with risk-based screening upon admission.MethodsThis observational study was conducted within a prospective cohort study. From January 1, 2018, until September 1, 2019, patients admitted to our hospital were asked to participate. Nasal and perianal samples were taken upon admission and checked for the presence of MDRO. The results of the universal risk assessment and risk-based screening were collected retrospectively from electronic health records.ResultsIn total, 1017 patients with 1069 separate hospital admissions participated in the study. Universal screening identified 38 (3.6%) unknown MDRO carriers upon admission (37 individual patients), all carrying extended-spectrum beta-lactamase-producing Enterobacterales. For 946 of 1069 (88.5%) patients, both the universal risk assessment and universal screening were performed. For 19 (2.0%) admissions, ≥1 risk factor was identified. The universal risk assessment identified one (0.1%) unknown carrier, compared to 37 out of 946 carriers for the universal screening (PConclusionsOur results show that in our low endemic setting, a universal screening strategy identified significantly more MDRO carriers than the currently implemented universal risk-assessment. When implementing a universal risk-assessment, risk factors should be carefully selected to be able to identify ESBL-E carriers. While the universal screening identified more MDRO carriers, further research is needed to determine the cost-effectiveness of this strategy.

Background: Autoimmune gastritis (AIG), characterized with the presence of anti-parietal-cell antibodies (APCA), is a risk factor for gastric cancer. However, AIG may go underdiagnosed, especially in the case of H. pylori infection and the presence of gastric precancerous lesions (GPL), due to the ambiguous pathology and delayed symptom onset. Aim: Investigate the prevalence and characteristics of AIG in GPL patients. Methods: Prevalence of AIG was determined with the presence of APCA in patients with GPL (n = 256) and the control group (n = 70). Pathological characteristics and levels of gastrin 17 (G17), pepsinogen (PG) I and II and anti-Helicobacter pylori IgG were assessed in GPL cases, and the severity of intestinal metaplasia and gastric atrophy was scored by expert pathologists. Results: APCA positivity was observed in 18% of cases vs. 7% of controls (p = 0.033). Only 3/256 patients were previously diagnosed with AIG. The presence of APCA was associated with corpus-limited and extended GPL. A receiver operating curve analysis demonstrated that the G17 and PGI/II ratio could identify APCA-positive patients within GPL cases (AUC: 0.884). Conclusions: The prevalence of AIG is higher in patients with GPL but goes undiagnosed. Using G17 and PG I/II as diagnostic markers can help to identify patients with AIG and improve surveillance programs for patients with GPL.

Toxicokinetic modelling provides a powerful tool in relating internal human exposure (i.e., assessed through urinary biomarker levels) to external exposure. Chemical specific toxicokinetic models are available; however, this specificity prevents their application to similar contaminants or to other routes of exposure. For this reason, we investigated whether a generic physiological-based kinetic (PBK) model might be a suitable alternative for a biokinetic model of deoxynivalenol (DON). IndusChemFate (ICF) was selected as a generic PBK model, which could be fit for purpose. Being suited for simulating multiple routes of exposure, ICF has particularly been used to relate the inhalation and dermal exposure of industrial chemicals to their urinary excretion. For the first time, the ICF model was adapted as a generic model for the human biomonitoring of mycotoxins, thereby extending its applicability domain. For this purpose, chemical-specific data for DON and its metabolites were collected directly from the literature (distribution and metabolism) or indirectly (absorption and excretion) by fitting the ICF model to previously described urinary excretion data. The obtained results indicate that this generic model can be used to model the urinary excretion of DON and its glucuronidated metabolites following dietary exposure to DON. Additionally, the present study establishes the basis for further development of the model to include an inhalation exposure route alongside the oral exposure route.

Abstract The student population has been highly vulnerable to the risk of mental health deterioration during the coronavirus disease (COVID-19) pandemic. This study aimed to reveal the prevalence and predictors of mental health among students in Poland, Slovenia, Czechia, Ukraine, Russia, Germany, Turkey, Israel, and Colombia in a socioeconomic context during the COVID-19 pandemic. The study was conducted among 2349 students (69% women) from May–July 2020. Data were collected by means of the Generalized Anxiety Disorder (GAD-7), Patient Health Questionnaire (PHQ-8), Perceived Stress Scale (PSS-10), Gender Inequality Index (GII), Standard & Poor's Global Ratings, the Oxford COVID-19 Government Response Tracker (OxCGRT), and a sociodemographic survey. Descriptive statistics and Bayesian multilevel skew-normal regression analyses were conducted. The prevalence of high stress, depression, and generalized anxiety symptoms in the total sample was 61.30%, 40.3%, and 30%, respectively. The multilevel Bayesian model showed that female sex was a credible predictor of PSS-10, GAD-7, and PHQ-8 scores. In addition, place of residence (town) and educational level (first-cycle studies) were risk factors for the PHQ-8. This study showed that mental health issues are alarming in the student population. Regular psychological support should be provided to students by universities.

Objectives: This prospective pilot study assessed the feasibility of cardiovascular magnetic resonance (CMR) imaging during biventricular (BIV) pacing in patients with a CMR conditional cardiac resynchronization therapy defibrillator (CRT-D) and compared the results with invasive volume measurements. Methods: Ten CRT-D patients underwent CMR imaging prior to device implantation (baseline) and six weeks after device implantation, including CRT-on and CRT-off modes. Left ventricular (LV) function, volumes, and strain measurements of LV dyssynchrony and dyscoordination were assessed. Invasive pressure–volume measurements were performed, matching the CRT settings used during CMR. Results: Post-implantation imaging enabled reliable cine assessment, but showed artefacts on late gadolinium enhancement images. After six weeks of CRT, significant reverse remodeling was observed, with a 22.7 ± 11% reduction in LV end-systolic volume during intrinsic rhythm (CRT-off). During CRT-on, the LV ejection fraction significantly improved from 27.4 ± 5.9% to 32.2 ± 8.7% (p < 0.01), and the strain assessment showed the abolition of the left bundle branch block contraction pattern. Invasively measured and CMR-assessed LV hemodynamics during BIV pacing were significantly associated. Conclusions: Post-CRT implantation CMR assessing acute LV pump function is feasible and provides important insights into the effects of BIV pacing on cardiac function and contraction patterns. LV assessment during CMR may constitute a future CRT optimization strategy.

Abstract During the various stages of shock loading, many transient modes of deformation can activate and deactivate to affect the final state of a material. In order to fundamentally understand and optimize a shock response, researchers seek the ability to probe these modes in real-time and measure the microstructural evolutions with nanoscale resolution. Neither post-mortem analysis on recovered samples nor continuum-based methods during shock testing meet both requirements. High-speed diffraction offers a solution, but the interpretation of diffractograms suffers numerous debates and uncertainties. By atomistically simulating the shock, X-ray diffraction, and electron diffraction of three representative BCC and FCC metallic systems, we systematically isolated the characteristic fingerprints of salient deformation modes, such as dislocation slip (stacking faults), deformation twinning, and phase transformation as observed in experimental diffractograms. This study demonstrates how to use simulated diffractograms to connect the contributions from concurrent deformation modes to the evolutions of both 1D line profiles and 2D patterns for diffractograms from single crystals. Harnessing these fingerprints alongside information on local pressures and plasticity contributions facilitate the interpretation of shock experiments with cutting-edge resolution in both space and time.

Abstract Background Aberrant changes in epigenetic mechanisms such as histone modifications play an important role in cancer progression. PRMT1 which triggers asymmetric dimethylation of histone H4 on arginine 3 (H4R3me2a) is upregulated in human colorectal cancer (CRC) and is essential for cell proliferation. However, how this dysregulated modification might contribute to malignant transitions of CRC remains poorly understood. Methods In this study, we integrated biochemical assays including protein interaction studies and chromatin immunoprecipitation (ChIP), cellular analysis including cell viability, proliferation, colony formation, and migration assays, clinical sample analysis, microarray experiments, and ChIP-Seq data to investigate the potential genomic recognition pattern of H4R3me2s in CRC cells and its effect on CRC progression. Results We show that PRMT1 and SMARCA4, an ATPase subunit of the SWI/SNF chromatin remodeling complex, act cooperatively to promote colorectal cancer (CRC) progression. We find that SMARCA4 is a novel effector molecule of PRMT1-mediated H4R3me2a. Mechanistically, we show that H4R3me2a directly recruited SMARCA4 to promote the proliferative, colony-formative, and migratory abilities of CRC cells by enhancing EGFR signaling. We found that EGFR and TNS4 were major direct downstream transcriptional targets of PRMT1 and SMARCA4 in colon cells, and acted in a PRMT1 methyltransferase activity-dependent manner to promote CRC cell proliferation. In vivo, knockdown or inhibition of PRMT1 profoundly attenuated the growth of CRC cells in the C57BL/6 J-ApcMin/+ CRC mice model. Importantly, elevated expression of PRMT1 or SMARCA4 in CRC patients were positively correlated with expression of EGFR and TNS4, and CRC patients had shorter overall survival. These findings reveal a critical interplay between epigenetic and transcriptional control during CRC progression, suggesting that SMARCA4 is a novel key epigenetic modulator of CRC. Our findings thus highlight PRMT1/SMARCA4 inhibition as a potential therapeutic intervention strategy for CRC. Conclusion PRMT1-mediated H4R3me2a recruits SMARCA4, which promotes colorectal cancer progression by enhancing EGFR signaling.

Abstract The pathophysiology behind thrombus formation in paroxysmal atrial fibrillation (AF) patients is very complex. This can be due to left atrial (LA) flow changes, remodeling, or both. We investigated differences for cardiovascular magnetic resonance (CMR)-derived LA 4D flow and remodeling characteristics between paroxysmal AF patients and patients without cardiac disease. In this proof-of-concept study, the 4D flow data were acquired in 10 patients with paroxysmal AF (age = 61 ± 8 years) and 5 age/gender matched controls (age = 56 ± 1 years) during sinus rhythm. The following LA and LA appendage flow parameters were obtained: flow velocity (mean, peak), stasis defined as the relative volume with velocities

Background: Lymph node involvement is the most important prognostic factor for recurrence and survival in vulvar cancer. Sentinel node (SN) procedure can be offered in well-selected patients with early vulvar cancer. This study aimed to assess current management practices with respect to the sentinel node procedure in women with early vulvar cancer in Germany. Methods: A Web-based survey was conducted. Questionnaires were e-mailed to 612 gynecology departments. Data were summarized as frequencies and analyzed using the chi-square test. Results: A total of 222 hospitals (36.27%) responded to the invitation to participate. Among the responders, 9.5% did not offer the SN procedure. However, 79.5% evaluated SNs by ultrastaging. In vulvar cancer of the midline with unilateral localized positive SN, 49.1% and 48.6% of respondents, respectively, would perform ipsilateral or bilateral inguinal lymph node dissection. Repeat SN procedure was performed by 16.2% of respondents. For isolated tumor cells (ITCs) or micrometastases, 28.1% and 60.5% of respondents, respectively, would perform inguinal lymph node dissection, whereas 19.3% and 23.8%, respectively, would opt for radiation without further surgical intervention. Notably, 50.9% of respondents would not initiate any further therapy and 15.1% would opt for expectant management. Conclusions: The majority of German hospitals implement the SN procedure. However, only 79.5% of respondents performed ultrastaging and only 28.1% were aware that ITC may affect survival in vulvar cancer. There is a need to ensure that the management of vulvar cancer follows the latest recommendations and clinical evidence. Deviations from state-of-the-art management should only be after a detailed discussion with the concerned patient.

ObjectivesThe current surveillance strategy in Barrett's esophagus (BE) uses only histological findings of the last endoscopy to assess neoplastic progression risk. As predictor values vary across endoscopies, single measurements may not be an accurate reflection. Our aim was to explore the value of using longitudinal evolutions (i.e. successive measurements) of histological findings (low-grade dysplasia (LGD)) and immunohistochemical biomarkers (p53 and SOX2) by investigating the association with Barrett's progression.MethodsIn this proof-of-principle study of a longitudinal dynamic risk estimation model with a multicenter cohort design, 631 BE patients from 15 Dutch hospitals who were under surveillance were included. Longitudinal dynamic values of LGD, p53, and SOX2 were included in a multivariate joint model to estimate the risk of high-grade dysplasia (HGD)/esophageal adenocarcinoma (EAC).ResultsLongitudinal evolutions of aberrant expression of p53 (HR 1.26, pConclusionsThis study provides solid ground to further explore a paradigm shift from currently recommended fixed intervals towards personalized surveillance, in which tailored risk estimations and corresponding surveillance intervals can be updated at every FU endoscopy for individual BE patients.

BackgroundEndometriosis is a chronic pain condition in premenopausal women. Pain is mainly characterized by pain intensity and may induce disability in all areas of daily life. Nevertheless, pain is influenced by emotional and social factors as well. Social distancing measures or quarantine, as reaction to rapidly rising infections with the COVID-19 virus due to the SARS-CoV-2 pandemic, were implemented across Europe to prevent the spread of the virus and social distancing measures were imposed by the German government by beginning of March 2020 with initiation of the lockdown by the end of March 2020. The objective of this study was to assess, how social distancing measures during the lockdown impacted the various aspects of pain perception in a group of chronic pain patients, such as women suffering from endometriosis.MethodsBetween 6th to 27th April 2020, an online questionnaire was activated at internet platforms of endometriosis patients support groups. Participants were asked retrospectively at one time point about their visual pain intensity measured by the visual analogue scale (VAS) and pain disability via pain disability index (PDI) prior to initiation of social distancing measures in Germany (VASP, PDIP), as well as the pain intensity and pain disability since implementation of social distancing measures (VASI, PDII). Differences of VAS and PDI previous and after implementation of social distancing measures were displayed as ΔVAS and ΔPDI. Pain experience and social support were assessed by a 5-point Likert scale.Results285 participants completed at least one question regarding pain intensity, disability, pain experience or social support. Dysmenorrhea, the symptom with the highest level of pain assessed by VAS, decreased significantly during the SARS-CoV-2 pandemic compared to the time period prior to social isolation (45.30% respondents experienced improvemenet vs 40.50% who experienced worsening; p = 0.025). The global physical impairment improved significantly (improvement of pain induced disability in 48.20% vs 40.90% with worsening of pain symptoms; p = 0.032) after the implementation of social distancing measures. Pain experience was negatively affected by social distancing measures, since frequency of pain awareness increased in 43.6% (pConclusionsPhysical pain and disability on one hand and emotional and social pain experience on the other were differentially affected by the emerged emotional, social and health care constraints related to the SARS-CoV-2 pandemic.

Background and aimThe reciprocal relation between falling and concern about falling is complex and not well understood. We aimed to determine whether concern about falling increases after a fall and whether concern about falling increases the odds of future falls in community-dwelling older adults without a recent fall history.MethodsWe selected 118 community-dwelling older adults (mean age: 71.4 (SD: 5.3) years) without a self-reported history of falling, one year prior to baseline assessment, from the one-year VIBE cohort for analyses. On a monthly basis, we recorded concern about falling (using the Falls Efficacy Scale-International, FES-I), as well as the occurrence of falls (through questionnaires and telephone calls). We determined 1) whether falling predicts an increase in concern about falling and 2) whether a high concern about falling is predictive of falling. Standard linear (fixed-effects) regression and mixed effects regression analyses were performed over long-term, i.e. one year, and short-term, i.e. one-month, intervals, respectively and were adjusted for gender, age and physical activity (quantified as the average total walking duration per day). Analyses were performed separately for all reported falls and for injurious falls only.ResultsHigh concern about falling at baseline did not predict falls over the course of one year, nor over the course of one month. Furthermore, falls in between baseline assessment and one year thereafter did not predict increased concern about falling from baseline to one year later, independent of whether all falls or only injurious falls were considered. However, falls, either all or injurious only, happening somewhere over the course of a one-month interval, significantly predicted small increases in concern about falling (1.49 FES-I points, 95% CI [0.74, 2.25], pConclusionOlder adults without a recent history of falling seem to be resilient against developing concern about falling after having fallen, resulting in a short-term temporary effect of falling on concern about falling. Furthermore, we found no evidence that a high concern about falling predicts future falls over a one-month or a one-year follow-up period, suggesting that concern is not a primary cause for falls in older adults without a recent history of falling.

The influence maximization problem (IMP) as classically formulated is based on the strong assumption that "chosen" nodes always adopt the new product. In this paper we propose a new influence maximization problem, referred to as the "Link-based Influence Maximization Problem" (LIM), which differs from IMP in that the decision variable of the spreader has changed from choosing an optimal seed to selecting an optimal node to influence in order to maximize the spread. Based on our proof that LIM is NP-hard with a monotonic increasing and submodular target function, we propose a greedy algorithm, GLIM, for optimizing LIM and use numerical simulation to explore the performance in terms of spread and computation time in different network types. The results indicate that the performance of LIM varies across network types. We illustrate LIM by applying it in the context of a Dutch national health promotion program for prevention of youth obesity within a network of Dutch schools. GLIM is seen to outperform the other methods in all network types at the cost of a higher computation time. These results suggests that GLIM may be utilized to increase the effectiveness of health promotion programs.

This study aimed to reveal differences in exposure to coronavirus disease (COVID-19) during the first (W1) and the second (W2) waves of the pandemic in six countries among university students and to show the prevalence and associations between exposure to COVID-19 and coronavirus-related post-traumatic stress syndrome (PTSD) risk during W2. The repeated cross-sectional study was conducted among university students from Germany, Poland, Russia, Slovenia, Turkey, and Ukraine (W1: n = 1684; W2: n = 1741). Eight items measured exposure to COVID-19 (regarding COVID-19 symptoms, testing, hospitalizing quarantine, infected relatives, death of relatives, job loss, and worsening economic status due to the COVID-19 pandemic). Coronavirus-related PTSD risk was evaluated by PCL-S. The exposure to COVID-19 symptoms was higher during W2 than W1 among students from all countries, except Germany, where, in contrast, the increase in testing was the strongest. Students from Poland, Turkey, and the total sample were more frequently hospitalized for COVID-19 in W2. In these countries, and Ukraine, students were more often in quarantine. In all countries, participants were more exposed to infected friends/relatives and the loss of a family member due to COVID-19 in W2 than W1. The increase in job loss due to COVID-19 was only noted in Ukraine. Economic status during W2 only worsened in Poland and improved in Russia. This was due to the significant wave of restrictions in Russia and more stringent restrictions in Poland. The prevalence of coronavirus-related PTSD risk at three cutoff scores (25, 44, and 50) was 78.20%, 32.70%, and 23.10%, respectively. The prediction models for different severity of PTSD risk differed. Female gender, a prior diagnosis of depression, a loss of friends/relatives, job loss, and worsening economic status due to the COVID-19 were positively associated with high and very high coronavirus-related PTSD risk, while female gender, a prior PTSD diagnosis, experiencing COVID-19 symptoms, testing for COVID-19, having infected friends/relatives and worsening economic status were associated with moderate risk.

Abstract Carbonate concretions are known to contain well-preserved fossils and soft tissues. Recently, biomolecules (e.g. cholesterol) and molecular fossils (biomarkers) were also discovered in a 380 million-year-old concretion, revealing their importance in exceptional preservation of biosignatures. Here, we used a range of microanalytical techniques, biomarkers and compound specific isotope analyses to report the presence of red and white blood cell-like structures as well as platelet-like structures, collagen and cholesterol in an ichthyosaur bone encapsulated in a carbonate concretion from the Early Jurassic (~182.7 Ma). The red blood cell-like structures are four to five times smaller than those identified in modern organisms. Transmission electron microscopy (TEM) analysis revealed that the red blood cell-like structures are organic in composition. We propose that the small size of the blood cell-like structures results from an evolutionary adaptation to the prolonged low oxygen atmospheric levels prevailing during the 70 Ma when ichthyosaurs thrived. The δ13C of the ichthyosaur bone cholesterol indicates that it largely derives from a higher level in the food chain and is consistent with a fish and cephalopod diet. The combined findings above demonstrate that carbonate concretions create isolated environments that promote exceptional preservation of fragile tissues and biomolecules.

The mental health of young adults, particularly students, is at high risk during the COVID-19 pandemic. The purpose of this study was to examine differences in mental health between university students in nine countries during the pandemic. The study encompassed 2349 university students (69% female) from Colombia, the Czech Republic (Czechia), Germany, Israel, Poland, Russia, Slovenia, Turkey, and Ukraine. Participants underwent the following tests: Patient Health Questionnaire (PHQ-8), Generalized Anxiety Disorder (GAD-7), Exposure to COVID-19 (EC-19), Perceived Impact of Coronavirus (PIC) on students’ well-being, Physical Activity (PA), and General Self-Reported Health (GSRH). The one-way ANOVA showed significant differences between countries. The highest depression and anxiety risk occurred in Turkey, the lowest depression in the Czech Republic and the lowest anxiety in Germany. The χ2 independence test showed that EC-19, PIC, and GSRH were associated with anxiety and depression in most of the countries, whereas PA was associated in less than half of the countries. Logistic regression showed distinct risk factors for each country. Gender and EC-19 were the most frequent predictors of depression and anxiety across the countries. The role of gender and PA for depression and anxiety is not universal and depends on cross-cultural differences. Students’ mental health should be addressed from a cross-cultural perspective.

Abstract Selection of microorganisms in marine sediment is shaped by energy-yielding electron acceptors for respiration that are depleted in vertical succession. However, some taxa have been reported to reflect past depositional conditions suggesting they have experienced weak selection after burial. In sediments underlying the Arabian Sea oxygen minimum zone (OMZ), we performed the first metagenomic profiling of sedimentary DNA at centennial-scale resolution in the context of a multi-proxy paleoclimate reconstruction. While vertical distributions of sulfate reducing bacteria and methanogens indicate energy-based selection typical of anoxic marine sediments, 5–15% of taxa per sample exhibit depth-independent stratigraphies indicative of paleoenvironmental selection over relatively short geological timescales. Despite being vertically separated, indicator taxa deposited under OMZ conditions were more similar to one another than those deposited in bioturbated intervals under intervening higher oxygen. The genomic potential for denitrification also correlated with palaeo-OMZ proxies, independent of sediment depth and available nitrate and nitrite. However, metagenomes revealed mixed acid and Entner-Dourdoroff fermentation pathways encoded by many of the same denitrifier groups. Fermentation thus may explain the subsistence of these facultatively anaerobic microbes whose stratigraphy follows changing paleoceanographic conditions. At least for certain taxa, our analysis provides evidence of their paleoenvironmental selection over the last glacial-interglacial cycle.

To date no informative biomarkers exist to accurately predict presence of lymph node metastases (LNM) in esophageal adenocarcinoma (EAC). We studied the discriminative value of Olfactomedin 4 (OLFM4), an intestinal stem cell marker, in EAC. Patients who had undergone esophagectomy as single treatment modality for both advanced (pT2-4) and early (pT1b) adenocarcinoma of the esophagus or gastro-esophageal junction were selected for this study from an institutional database (Erasmus MC University Medical Center, Rotterdam, The Netherlands). Surgical resection specimens of 196 advanced and 44 early EAC were examined. OLFM4 expression was studied by immunohistochemistry and categorized as low ( = 30%) expression. Low OLFM4 was associated with poor differentiation grade in both advanced (60% vs. 34.8%, p = 0.001) and early EAC (39.1% vs. 9.5%, p = 0.023). LNM were present in 161 (82.1%) of advanced and 9 (20.5%) of early EAC respectively. Low OLFM4 was independently associated with the presence of LNM in advanced EAC in multivariable analysis (OR 2.7; 95% CI, 1.16-6.41; p = 0.022), but not in early EAC (OR 2.1; 95% CI, 0.46-9.84; p = 0.338). However, the difference in association with LNM between advanced (OR 2.7; 95% CI, 1.18-6.34; p = 0.019) and early (OR 2.3; 95% CI, 0.47-11.13; p = 0.302) EAC was non-significant (p = 0.844), suggesting that the lack of significance in early EAC is due to the small number of patients in this group. OLFM4 was not of significance for the disease free and overall survival. Overall, low expression of intestinal stem cell marker OLFM4 was associated with the presence of LNM. Our study suggests that OLFM4 could be an informative marker with the potential to improve preoperative assessment in patients with EAC. Further studies are needed to confirm the value of OLFM4 as a biomarker for LNM.

The scientific data to guide the management of Peutz–Jeghers syndrome (PJS) are sparse. The available evidence has been reviewed and discussed by diverse medical specialists in the field of PJS to update the previous guideline from 2010 and formulate a revised practical guideline for colleagues managing PJS patients. Methods: Literature searches were performed using MEDLINE, Embase, and Cochrane. Evidence levels and recommendation strengths were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). A Delphi process was followed, with consensus being reached when ≥80% of the voting guideline committee members agreed. Recommendations and statements: The only recent guidelines available were for gastrointestinal and pancreatic management. These were reviewed and endorsed after confirming that no more recent relevant papers had been published. Literature searches were performed for additional questions and yielded a variable number of relevant papers depending on the subject addressed. Additional recommendations and statements were formulated. Conclusions: A decade on, the evidence base for recommendations remains poor, and collaborative studies are required to provide better data about this rare condition. Within these restrictions, multisystem, clinical management recommendations for PJS have been formulated.