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Artificial intelligence (AI) holds significant potential for enhancing quality of gastrointestinal (GI) endoscopy, but the adoption of AI in clinical practice is hampered by the lack of rigorous standardisation and development methodology ensuring generalisability. The aim of the Quality Assessment of pre-clinical AI studies in Diagnostic Endoscopy (QUAIDE) Explanation and Checklist was to develop recommendations for standardised design and reporting of preclinical AI studies in GI endoscopy.The recommendations were developed based on a formal consensus approach with an international multidisciplinary panel of 32 experts among endoscopists and computer scientists. The Delphi methodology was employed to achieve consensus on statements, with a predetermined threshold of 80% agreement. A maximum three rounds of voting were permitted.Consensus was reached on 18 key recommendations, covering 6 key domains: data acquisition and annotation (6 statements), outcome reporting (3 statements), experimental setup and algorithm architecture (4 statements) and result presentation and interpretation (5 statements). QUAIDE provides recommendations on how to properly design (1. Methods, statements 1–14), present results (2. Results, statements 15–16) and integrate and interpret the obtained results (3. Discussion, statements 17–18).The QUAIDE framework offers practical guidance for authors, readers, editors and reviewers involved in AI preclinical studies in GI endoscopy, aiming at improving design and reporting, thereby promoting research standardisation and accelerating the translation of AI innovations into clinical practice.

Background and aim: Moderate and late preterm infants (MLPTI) (gestational age 32 0/7–36 6/7 weeks), are at risk for suboptimal growth. This study evaluated adherence to nutritional recommendations until 6 months corrected age (CA), growth until 2 years CA, and associations between nutritional intake and growth until 2 years CA. Methods: We prospectively collected nutritional intakes from 100 MLPTI during the first week of life and at 6 weeks, 3 months, and 6 months CA. Anthropometry was assessed at birth, discharge, term age, and at 6 weeks, 3 months, 6 months, 1 year, and 2 years CA. Results: On day 7, <40% reached nutritional recommendations. Thereafter, >80% reached protein recommendations until 6 months of life, but <60% reached energy recommendations. Weight z-scores increased from −0.44 at term-age to 0.59 at 3 months CA, but declined to −0.53 at 2 years CA on the TNO curves. No significant associations were found between nutritional intake and growth until 2 years CA. Conclusion: No associations were demonstrated between nutritional intakes and growth until 2 years CA, despite not reaching recommended intakes. Despite high efforts to optimize growth, MLPTI find their own growth curve in the first 2 years of life. Impact:

This research is pioneering in identifying how nutrition influences growth in moderate and late preterm infants (MLPTI) up to 2 years corrected age (CA).

MLPTI often do not meet the recommended protein and energy intake in their first week of life, suggesting that current guidelines might be too high.

No association was demonstrated between nutritional intake and growth of MLPTI in the first 2 years of life.

Initially, MLPTI show an increase in weight z-scores from term age up to 3 months CA but experience a decline in weight z-scores at 2 years CA, according to TNO growth charts.

Computer-aided detection (CADe) systems could assist endoscopists in detecting early neoplasia in Barrett's oesophagus, which could be difficult to detect in endoscopic images. The aim of this study was to develop, test, and benchmark a CADe system for early neoplasia in Barrett's oesophagus.

Background: The repair of inguinal hernias is a common surgical procedure. Some patients will need a second operation after developing a metachronous contralateral inguinal hernia (MCIH). The suggestion has been made to strengthen the contralateral side at the same time as primary unilateral surgery. In this systematic review we aim to determine how many adult patients with a unilateral inguinal hernia will develop a MCIH. Methods: This review was reported in line with PRISMA guidelines. We performed a literature review in PubMed Publisher, Embase, Google Scholar and Cochrane Library until May 2021, including articles reporting MCIH after unilateral inguinal hernia repair in adults. As outcome measure, the number of patients diagnosed with a MCIH was registered. Results: A total of 19 articles with a total of 277,288 patients were included. The combined estimate for MCIH after meta-analysis equaled 8.3% (95% CI 7.1%–9.5%), with a high index of heterogeneity (I2= 97.9%). A random-effects meta-regression was performed to obtain the percentage of MCIH as a function of median follow-up time. The percentage of MCIH at 3, 5 and 10 years was estimated at 5.2%, 8.0% and 17.1%, respectively. Conclusion: We suggest that there is insufficient clinical evidence to support prophylactic contralateral repair in all patients. We propose a patient-specific approach in the decision to perform prophylactic repair, taking into account potential risk factors for hernia development, type of surgical approach, and general risk factors for chronic postoperative inguinal pain. More long-term prospective data are needed to guide the decision for prophylactic contralateral mesh placement.

ABSTRACTIntroductionMonoclonal antibodies have revolutionized personalized medicine for cancer in recent decades. Despite their broad application in oncology, their large size and complexity may interfere with successful tumor targeting for certain applications of cancer diagnosis and therapy. Nanobodies have unique structural and pharmacological features compared to monoclonal antibodies and have successfully been used as complementary anti-cancer diagnostic and/or therapeutic tools.Areas coveredHere, an overview is given of the nanobody-based diagnostics and therapeutics that have been or are currently being tested in oncological clinical trials. Furthermore, preclinical developments, which are likely to be translated into the clinic in the near future, are highlighted.Expert opinionOverall, the presented studies show the application potential of nanobodies in the field of oncology, making it likely that more nanobodies will be clinically approved in the upcoming future.

Barrett's esophagus (BE) is a known precursor for esophageal adenocarcinoma. Despite advances in endoscopic imaging modalities, endoscopic detection of BE neoplasia remains challenging, with considerable miss rates. Over the past years, artificial intelligence (AI) has emerged as a promising tool that may be a useful adjunct to the endoscopist. In this review, we provide an overview of the current role of AI in the management of BE and elaborate on the key challenges that need be addressed to enable its successful integration into daily endoscopic practice.

Background: Patients undergoing unilateral inguinal hernia repair (IHR) are at risk of metachronous contralateral inguinal hernia (MCIH) development. We evaluated incidence and risk factors of MCIH development up to 25 years after unilateral IHR to determine possible indications for concomitant prophylactic surgery of the contralateral groin at the time of primary surgery. Methods: Patients between 18 and 70 years of age undergoing elective unilateral IHR in the University Hospital of Leuven from 1995 to 1999 were studied retrospectively using the electronic health records and prospectively via phone calls. Study aims were MCIH incidence and risk factor determination. Kaplan–Meier curves were constructed and univariable and multivariable Cox regressions were performed. Results: 758 patients were included (91% male, median age 53 years). Median follow-up time was 21.75 years. The incidence of operated MCIH after 5 years was 5.6%, after 15 years 16.1%, and after 25 years 24.7%. The incidence of both operated and non-operated MCIH after 5 years was 5.9%, after 15 years 16.7%, and after 25 years 29.0%. MCIH risk increased with older age and decreased in primary right-sided IHR and higher BMI at primary surgery. Conclusion: The overall incidence of MCIH after 25-year follow-up is 29.0%. Potential risk factors for the development of a MCIH are primary left-sided inguinal hernia repair, lower BMI, and older age. When considering prophylactic repair, we suggest a patient-specific approach taking into account these risk factors, the surgical approach and the risk factors for chronic postoperative inguinal pain.

Pupils’ and students’ learning in the workplace and dual education has drawn increased attention because it is, among others, relevant in combating youth unemployment, increasing individual employability, and organisations’ ability to provide high quality services and products. However, research focusing on pupils’ and students’ readiness to participate in learning in the workplace is scarce and scattered. The present study was conducted to get a deeper insight into readiness to participate in learning in the workplace, and more particular in the Flemish (Belgium) context of dual education. The study applied a multi-method approach including literature review, document study, semi-structured interviews and member checking. The study resulted in a conceptualisation of ‘willingness to participate in learning in the workplace’ and ‘maturity for learning in the workplace’ including clusters of competencies related to participation in the workplace, learning in the workplace, and motivation for learning and participating in the workplace. This conceptualisation contributes to the development of policy and practice through providing a basis for assessing readiness to participate in dual education.

Background: The availability of glutathione, the main intracellular antioxidant, is compromised in preterm neonates. A possible explanation is the low availability of substrate for synthesis, because many neonatologists are reluctant to administer amino acids in the direct postnatal period for fear of intolerance. Objective: The objective of the study was to determine the effects of amino acid administration directly after birth on glutathione synthesis rates and markers of oxidative stress. Design: Premature infants (< 1500 g) received from birth onward either dextrose (control group; n = 10) or dextrose plus 2.4 g amino acids x [kg.sup.-1] x [d.sup.-1] (intervention group; n = 10). On postnatal day 2, [1-[sup.13]C]glycine was administered to determine glutathione fractional synthesis rates ([FSR.sub.GSH]) and absolute synthesis rates ([ASR.sub.GSH]) in erythrocytes. In plasma, advanced oxidized protein products and dityrosine, both markers of oxidative stress, were measured. The results are expressed as means [+ or -] SDs. Results: The [FSR.sub.GSH] was not different between groups: 44 [+ or -] 6 and 48 [+ or -] 9%/d in the control and intervention groups, respectively (P = 0.28). The concentration of erythrocyte glutathione was higher (P < 0.001) in the intervention group (2.28 [+ or -] 0.35 mmol/L) than in the control group (1.73 [+ or -] 0.37 mmol/L). [ASR.sub.GSH] values were 6.5 [+ or -] 1.5 and 11.3 [+ or -] 1.9 mg x [kg.sup.-1] x [d.sup.-1] in the control and intervention groups, respectively (P < 0.001). Advanced oxidized protein products and dityrosine concentrations were not significantly different between groups. Conclusions: Amino acid administration directly after birth increases [ASR.sub.GSH] in preterm infants. Our data are consistent, however, with higher glutathione concentrations rather than a higher [FSR.sub.GSH]. Greater availability of glutathione, nevertheless, did not decrease markers of oxidative stress.

Many studies have been conducted to examine the predictors of fear of crime among adults, but feelings of insecurity among children and adolescents have been practically ignored. The aim of this study is to search for relevant determinants of fear of crime in a representative sample of 1,212 Flemish (Belgian) adolescents, age 14 to 18, and one of their parents. The effect of parenting styles on the child's level of fear is investigated by means of (multigroup) structural equation modeling. The level of parental supervision (especially fathers) is associated with more fears being experienced by children. Active parental stimulation of participation in organized leisure activities results in lower levels of fear among female children. Parents who focus on independence and autonomy, in contrast, seem to raise boys who have lower degrees of fear. Other findings that relate to fear of crime in adolescence, such as gender differences and socialization, media and leisure patterns, and victimization and personal adjustment, are also discussed. Keywords: fear of crime; feelings of insecurity; parenting styles; adolescence; gender

The LIR!C trial showed that laparoscopic ileocaecal resection is a cost-effective treatment that has similar quality-of-life outcomes to treatment with infliximab, an anti-tumour necrosis factor (TNF) drug. We aimed to compare long-term outcomes of both interventions and identify baseline factors associated with the duration of treatment effect in each group.

Background and aims: Early gastric cancer (EGC) lesions are often subtle and endoscopically poorly visible. The aim of this study is to evaluate the additive effect of linked color imaging (LCI) next to white-light endoscopy (WLE) for identification of EGC, when assessed by expert and non-expert endoscopists. Methods: Forty EGC cases were visualized in corresponding WLE and LCI images. Endoscopists evaluated the cases in 3 assessment phases: Phase 1: WLE images only; Phase 2: LCI images only; Phase 3: WLE and LCI images side-to-side. First, 3 expert endoscopists delineated all cases. A high level of agreement between the expert delineations corresponded with a high AND/OR ratio. Subsequently, 62 non-experts indicated their preferred biopsy location. Outcomes of the study are as follows: (1) difference in expert AND/OR ratio; (2) accuracy of biopsy placement by non-expert endoscopists; and (3) preference of imaging modality by non-expert endoscopists. Results: Quantitative agreement between experts increased significantly when LCI was available (0.58 vs. 0.46, p= 0.007). This increase was more apparent for the more challenging cases (0.21 vs. 0.47, p&lt; 0.001). Non-experts placed the biopsy mark more accurately with LCI (82.3% vs. 87.2%, p&lt; 0.001). Again this increase was more profound for the more challenging cases (70.4% vs. 83.4%, p&lt; 0.001). Non-experts indicated to prefer LCI over WLE. Conclusion: The addition of LCI next to WLE improves visualization of EGC. Experts reach higher consensus on discrimination between neoplasia and inflammation when using LCI. Non-experts improve their targeted biopsy placement with the use of LCI. LCI therefore appears to be a useful tool for identification of EGC. Graphical abstract:

Because the current Barrett’s esophagus (BE) surveillance protocol suffers from sampling error of random biopsies and a high miss-rate of early neoplastic lesions, many new endoscopic imaging and sampling techniques have been developed. None of these techniques, however, have significantly increased the diagnostic yield of BE neoplasia. In fact, these techniques have led to an increase in the amount of visible information, yet endoscopists and pathologists inevitably suffer from variations in intra- and interobserver agreement. Artificial intelligence systems have the potential to overcome these endoscopist-dependent limitations.

Herpesviruses are ubiquitous pathogens that establish lifelong, latent infections in their host. Spontaneous reactivation of herpesviruses is often asymptomatic or clinically manageable in healthy individuals, but reactivation events in immunocompromised or immunosuppressed individuals can lead to severe morbidity and mortality. Moreover, herpesvirus infections have been associated with multiple proliferative cardiovascular and post-transplant diseases. Herpesviruses encode viral G protein–coupled receptors (vGPCRs) that alter the host cell by hijacking cellular pathways and play important roles in the viral life cycle and these different disease settings. In this review, we discuss the pharmacological and signaling properties of these vGPCRs, their role in the viral life cycle, and their contribution in different diseases. Because of their prominent role, vGPCRs have emerged as promising drug targets, and the potential of vGPCR-targeting therapeutics is being explored. Overall, these vGPCRs can be considered as attractive targets moving forward in the development of antiviral, cancer, and/or cardiovascular disease treatments.Significance StatementIn the last decade, herpesvirus-encoded G protein–coupled receptors (GPCRs) have emerged as interesting drug targets with the growing understanding of their critical role in the viral life cycle and in different disease settings. This review presents the pharmacological properties of these viral receptors, their role in the viral life cycle and different diseases, and the emergence of therapeutics targeting viral GPCRs.

Treatment of patients with ileocaecal Crohn's disease who have not responded to conventional therapy is commonly scaled up to biological agents, but surgery can also offer excellent short-term and long-term results. We compared laparoscopic ileocaecal resection with infliximab to assess how they affect health-related quality of life.

There has been a vast increase in GI literature focused on the use of machine learning in endoscopy. The relative novelty of this field poses a challenge for reviewers and readers of GI journals. To appreciate scientific quality and novelty of machine learning studies, understanding of the technical basis and commonly used techniques is required. Clinicians often lack this technical background, while machine learning experts may be unfamiliar with clinical relevance and implications for daily practice. Therefore, there is an increasing need for a multidisciplinary, international evaluation on how to perform high-quality machine learning research in endoscopy. This review aims to provide guidance for readers and reviewers of peer-reviewed GI journals to allow critical appraisal of the most relevant quality requirements of machine learning studies. The paper provides an overview of common trends and their potential pitfalls and proposes comprehensive quality requirements in six overarching themes: terminology, data, algorithm description, experimental setup, interpretation of results and machine learning in clinical practice.

Photodynamic therapy (PDT) eradicates tumors by the local activation of a photosensitizer with near-infrared light. One of the aspects hampering the clinical use of PDT is the poor selectivity of the photosensitizer. To improve this, we have recently introduced a new approach for targeted PDT by conjugating photosensitizers to nanobodies. Diverse G protein-coupled receptors (GPCRs) show aberrant overexpression in tumors and are therefore interesting targets in cancer therapy. Here we show that GPCR-targeting nanobodies can be used in targeted PDT. We have developed a nanobody binding the extracellular side of the viral GPCR US28, which is detected in tumors like glioblastoma. The nanobody was site-directionally conjugated to the water-soluble photosensitizer IRDye700DX. This nanobody–photosensitizer conjugate selectively killed US28-expressing glioblastoma cells both in 2D and 3D cultures upon illumination with near-infrared light. This is the first example employing a GPCR as target for nanobody-directed PDT. With the emerging role of GPCRs in cancer, this data provides a new angle for exploiting this large family of receptors for targeted therapies.

Recent developments in the gig economy triggered labour law. Platforms change the relationship between customers and workers causing over-subordination of workers. The over-subordination is caused by customers and the surveys they complete to evaluate the worker. The influence of customers over workers can also be seen in a more traditional setting. However, customers are not always king. It is suggested in this article that surveys can be used as an instrument to build decent labour relationships. Installing the measurement of needs measures the impact of customers on workers. By installing a continuous measure of the needs, we have at our disposal an instrument to fulfil labour law’s wellbeing function. Labour legislation could oblige employers to integrate need satisfaction into their customer surveys and their workers surveys. By doing so, technology allows us to make sure that platform work or any kind of work where workers meet high customer demands, become ‘Innovative forms of work that ensure quality working conditions’, as requested by the European Social Pillar.

ObjectiveEvaluate the cost-effectiveness of laparoscopic ileocaecal resection compared with infliximab in patients with ileocaecal Crohn’s disease failing conventional therapy.DesignA multicentre randomised controlled trial was performed in 29 centres in The Netherlands and the UK. Adult patients with Crohn’s disease of the terminal ileum who failed >3 months of conventional immunomodulators or steroids without signs of critical strictures were randomised to laparoscopic ileocaecal resection or infliximab. Outcome measures included quality-adjusted life-years (QALYs) based on the EuroQol (EQ) 5D-3L Questionnaire and the Inflammatory Bowel Disease Questionnaire (IBDQ). Costs were measured from a societal perspective. Analyses were performed according to the intention-to-treat principle. Missing cost and effect data were imputed using multiple imputation. Cost-effectiveness planes and cost-effectiveness acceptability curves were estimated to show uncertainty.ResultsIn total, 143 patients were randomised. Mean Crohn’s disease total direct healthcare costs per patient at 1 year were lower in the resection group compared with the infliximab group (mean difference €−8931; 95% CI €−12 087 to €−5097). Total societal costs in the resection group were lower than in the infliximab group, however not statistically significant (mean difference €−5729, 95% CI €−10 606 to €172). The probability of resection being cost-effective compared with infliximab was 0.96 at a willingness to pay (WTP) of €0 per QALY gained and per point improvement in IBDQ Score. This probability increased to 0.98 at a WTP of €20 000/QALY gained and 0.99 at a WTP of €500/point of improvement in IBDQ Score.ConclusionLaparoscopic ileocaecal resection is a cost-effective treatment option compared with infliximab.Clinical trial registration numberDutch Trial Registry NTR1150; EudraCT number 2007-005042-20 (closed on 14 October 2015).

Dysregulation of the chemokine system is implicated in a number of autoimmune and inflammatory diseases, as well as cancer. Modulation of chemokine receptor function is a very promising approach for therapeutic intervention. Despite interest from academic groups and pharmaceutical companies, there are currently few approved medicines targeting chemokine receptors. Monoclonal antibodies (mAbs) and antibody-based molecules have been successfully applied in the clinical therapy of cancer and represent a potential new class of therapeutics targeting chemokine receptors belonging to the class of G protein–coupled receptors (GPCRs). Besides conventional mAbs, single-domain antibodies and antibody scaffolds are also gaining attention as promising therapeutics. In this review, we provide an extensive overview of mAbs, single-domain antibodies, and other antibody fragments targeting CXCR4 and ACKR3, formerly referred to as CXCR7. We discuss their unique properties and advantages over small-molecule compounds, and also refer to the molecules in preclinical and clinical development. We focus on single-domain antibodies and scaffolds and their utilization in GPCR research. Additionally, structural analysis of antibody binding to CXCR4 is discussed.SIGNIFICANCE STATEMENTModulating the function of GPCRs, and particularly chemokine receptors, draws high interest. A comprehensive review is provided for monoclonal antibodies, antibody fragments, and variants directed at CXCR4 and ACKR3. Their advantageous functional properties, versatile applications as research tools, and use in the clinic are discussed.

An EIT shutterless campaign was conducted on 11 July 2001 and provided 120 high-cadence (68 s) 30.4 nm images of the north-eastern quarter of the Sun. Systematic intensity variations are seen which appear to propagate along an off-disk loop-like structure. In this paper we study the nature of these intensity variations by confronting the EIT observations studied in De Groof et al. (2004, A&A, 415, 1141) with simultaneous Hαimages from Big Bear Solar Observatory. With the goal to carefully co-register the two image sets, we introduce a technique designed to compare data of two different instruments. The image series are first co-aligned and later overplotted in order to visualize and compare the behaviour of the propagating disturbances in both data sets. Since the same intensity variations are seen in the EIT 30.4 nm and in the Hαimages, we confirm the interpretation of De Groof et al. (2004, A&A, 415, 1141) that we are observing downflows of relatively cool plasma. The origin of the downflows is explained by numerical simulations of “catastrophic cooling” in a coronal loop which is heated predominantly at its footpoints.

At high spatial and temporal resolution, coronal loops are observed to have a highly dynamic nature. Recent observations with SOHO and TRACE frequently show localized brightenings “raining” down towards the solar surface. What is the origin of these features? Here we present for the first time a comparison of observed intensity enhancements from an EIT shutterless campaign with non-equilibrium ionization simulations of coronal loops in order to reveal the physical processes governing fast flows and localized brightenings. We show that catastrophic cooling around the loop apex as a consequence of footpoint-concentrated heating offers a simple explanation for these observations. An advantage of this model is that no external driving mechanism is necessary as the dynamics result entirely from the non-linear character of the problem.

On 11 July 2001 an EIT shutterless campaign was conducted which provided 120 high-cadence (68 s) 304 Å images of the north eastern quarter of the Sun. The most interesting feature seen in the data is an off-limb half loop structure along which systematic intensity variations are seen which appear to propagate from the top of the loop towards its footpoint. We investigate the underlying cause of these propagating disturbances, i.e. whether they are caused by waves or by plasma flows. First we identify 7 blobs with the highest intensities and follow them along the loop. By means of a location-time plot, bulk velocities can be measured at several locations along the loop. The velocity curve found this way is then compared with characteristic wave speeds and with the free-fall speed in order to deduce the nature of the intensity variations. Additional information on density and temperature is derived by measuring the relative intensity enhancements and comparing the EIT 304 Å sequence with Big Bear data and 171 Å data (TRACE/EIT). The combination of all these constraints gives us an insight on the nature and origin of these intensity variations. The idea of slow magneto-acoustic waves is rejected, and we find several arguments supporting that these intensity variations are due to flowing/falling plasma blobs.

IL6-related T cell activation and TNFα-dependent cell proliferation are major targets of therapy in the RA synovium. We investigated whether expression of these pathways in RA synovial biopsies is associated with disease activity and response to therapy. Correlation and gene set enrichment studies were performed using gene expression profiles from RA synovial biopsies. Immunostaining experiments of GADD45B and PDE4D were performed on independent additional sets of early untreated RA samples, obtained in two different centers by needle-arthroscopy or US-guided biopsies. In 65 RA synovial biopsies, transcripts correlating with disease activity were strongly enriched in TNFα-induced genes. Out of the individual variables used in disease-activity scores, tender joint count, swollen joint count and physician’s global assessment, but not CRP or patient’s global assessment displayed a similar correlation with the expression of TNFα-dependent genes. In addition, TNFα-induced genes were also significantly enriched in transcripts over-expressed in synovial biopsy samples obtained from poor-responders to methotrexate or tocilizumab, prior to initiation of therapy. GADD45B (induced by TNFα in monocytes) and PDE4D (induced by TNFα in FLS) immunostaining was significantly higher in overall poor-responders to therapy in 46 independent baseline samples obtained from early untreated RA patients prior to initiation of therapy. GADD45B (but not PDE4D) immunostaining was significantly higher in the sub-group of patients with poor-response to methotrexate therapy, and this was confirmed in another population of methotrexate-treated patients. Higher expression of TNFα-induced transcripts in early RA synovitis is associated with higher disease activity, and predicts poor response to first-line therapy. That over-expression of TNFα-induced genes predicts poor-response to therapy regardless of the drug administered, indicates that this molecular signature is associated with disease severity, rather than with specific pathways of escape to therapy.

The article discusses the importance of microorganisms for wastewater treatment. Topics mentioned include the prominence of activated sludge process for treatment of industrial and domestic wastewater, the role of biological reactors as support for microbial populations, and the benefits of enzymes for biological reactions.

The excitation of Alfvén and fast magneto-acoustic waves in coronal loops driven by footpoint motions is studied in linear, ideal MHD. The analysis is restricted to azimuthally polarized footpoint motions so that only Alfvén waves are directly excited which couple to fast magneto-acoustic waves at later times. In the present study a periodic driver is applied at one end of the loop. The effects of a more realistic random driver are studied in the companion paper De Groof & Goossens (2002) (hereafter referred to as Paper II). The first part of the paper is devoted to the study of resonant absorption and phase-mixing in the absence of coupling (azimuthal wavenumber ky=0). Since the density varies across the loop, resonances occur at the magnetic surfaces where the driving frequency equals the local Alfvén frequency. In a second part where Alfvén waves with $k_y \neq 0$coupling to fast waves are taken into account, we find that the behaviour of the MHD waves is strongly dependent on the driving frequency $\omega_{\rm d}$. Especially driving frequencies equal to a quasi-mode frequency seem to make the difference. The fast waves excited in these cases are global oscillations of the system and form quasi-modes as they are damped through the resonant coupling with Alfvén modes. Since these resonances occur at the same location where the original Alfvén wave peaks, the resonant peak is further amplified. While in most cases coupling has a negative effect on the growth of the directly excited Alfvén waves, driving with a quasi-mode frequency leads to a faster growth of the resonant peaks and a more efficient decrease in length scales than in the uncoupled case.

The definition of working time has been the subject of case law of the European Court of Justice (CJEU) many times before. A recent judgement of the CJEU on the time spent travelling by mobile workers adds a new piece to the puzzle. After describing the case, this commentary will make an attempt to clarify its impact on the concept of working time by looking at other situations where employees have to travel from their homes to customers. Afterwards, arguments are given as to why this judgement could perhaps be seen as a new CJEU puzzle altogether regarding the definition of working time by comparing this case to the well-established case law of the CJEU on doctors on call.

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Perianal fistulas are categorized as “complex” under the following conditions: a high tract passing the upper two-thirds of the external sphincter, presence of multiple fistula tracts, rectovaginal fistulas, previous local irradiation, and association with the presence of an anorectal stricture or Crohn׳s disease. Treatment of complex fistulas can be challenging and carries a high risk of poor wound healing, recurrences, and incontinence. Therefore a detailed understanding of perianal anatomy, knowledge of the extent of the disease, and its relation to the various structures are required for proper management. This article describes the technical approach of various advanced soft tissue techniques for complex fistula repair (i.e., the endorectal mucosal advancement flap, the anocutaneous advancement flap, and the Martius flap) and discusses its indications, advantages, and associated complications. The reported success rates of endorectal advancement flaps in the literature are variable, but generally better for cryptoglandular (24–100%) compared to Crohn׳s (33–92%) fistulas. The success rate in patients with Crohn׳s disease appears to be slightly better under anti-TNF therapy. Sphincteroplasty following complete fistulotomy (episioproctotomy) can be an appropriate approach in a selected patient group. In conclusion, treatment of complex perianal fistulas is challenging, and the advanced soft tissue techniques are an important option within the armamentarium of techniques that can be applied to treat this condition in a patient-tailored treatment approach.

Background:We determined the effect of adaptation to the study diet on oxidation of the indicator amino acid and the required tracer washout time in preterms.Methods:Subjects received a study diet for 6 d that entailed a 50% reduction in leucine. Tracer studies using enterally infused [13C]bicarbonate and [1-13C]phenylalanine were performed on days 1, 2, 4, and 6. Breath samples containing 13CO2were collected during steady state and measured by infrared spectrometric analysis, and the fraction of 13CO2recovery from 13C oxidation (F13CO2) was calculated.Results:Preterm infants (n = 11, birth weight 1.9 ± 0.1?kg, gestational age 32.6 ± 1.5?wk) received 166?mg/kg/d of leucine. Baseline enrichment changed significantly at day 1 of the study diet. F13CO2did not change significantly between days 2 and 4 but was significantly lower at day 6. The tracer washout time was determined to be 7.5?h using a biphasic regression analysis.Conclusion:One day of adaptation to a new diet is necessary to adapt to the 13C enrichment of the study formula before starting infant requirement studies. Adaptation for a period of 5 d results in a protein-sparing response. The minimal time between two studies within the same subject is 7.5?h.

Presenilin-1 (PS1) and −2 (PS2), which when mutated cause familial Alzheimer disease, have been localized to numerous compartments of the cell, including the endoplasmic reticulum, Golgi, nuclear envelope, endosomes, lysosomes, the plasma membrane, and mitochondria. Using three complementary approaches, subcellular fractionation, γ-secretase activity assays, and immunocytochemistry, we show that presenilins are highly enriched in a subcompartment of the endoplasmic reticulum that is associated with mitochondria and that forms a physical bridge between the two organelles, called endoplasmic reticulum-mitochondria-associated membranes. A localization of PS1 and PS2 in mitochondria-associated membranes may help reconcile the disparate hypotheses regarding the pathogenesis of Alzheimer disease and may explain many seemingly unrelated features of this devastating neurodegenerative disorder.

ABSTRACTIntracellular pathogenic organisms such as salmonellae and shigellae are able to evade the effects of many antibiotics because the drugs are not able to penetrate the plasma membrane. In addition, these bacteria may be able to transfer genes within cells while protected from the action of drugs. The primary mode by which virulence and antibiotic resistance genes are spread is bacterial conjugation. Salmonellae have been shown to be competent for conjugation in the vacuoles of cultured mammalian cells. We now show that the conjugation machinery is also functional in the mammalian cytosol. Specially constructed Escherichia colistrains expressing Shigella flexneriplasmid and chromosomal virulence factors for escape from vacuoles and synthesizing the invasin protein from Yersinia pseudotuberculosisto enhance cellular entry were able to enter 3T3 cells and escape from the phagocytic vacuole. One bacterial strain (the donor) of each pair to be introduced sequentially into mammalian cells had a conjugative plasmid. We found that this plasmid could be transferred at high frequency. Conjugation in the cytoplasm of cells may well be a general phenomenon.

In explanations offered for fear of crime, two different paradigms can be distinguished. The first considers fear of crime as a rational reaction to crime and victimization; the other views such fear as a representation of more general feelings of malaise. The paradigms suggest different research strategies and offer different explanations for the same empirical observations. The choice of paradigm therefore determines the meaning of the empirical findings and hence the policy implications that can be drawn from them. In this article, the authors describe the paradigms, illustrate the way in which they offer different explanations for the same observations, and try to empirically discriminate between them on the basis of crucial tests. The tests are performed on data for the Flemish (Belgian) population aged nineteen to thirty-six. The results support the view that fear of crime or feelings of insecurity should be seen mainly as a consequence of, on one hand, general feelings of malaise, vulnerability, and helplessness that can have many origins and, on the other hand, exposure to processes of communication that highlight crime and the risk of victimization.

AbstractSimulations of Coronal Mass Ejections (CMEs) evolving in the interplanetary (IP) space from the Sun up to 1 AU are performed in the framework of ideal magnetohydrodynamics (MHD). The aim is to quantify the effect of the background solar wind and of the CME initiation parameters on the evolution and on the geo-effectiveness of CMEs. The shocks and magnetic clouds related to fast CMEs in the solar corona and interplanetary space play a crucial role in the study of space weather. Better predictions of space weather events require a deeper insight in the physics behind them. Different solar wind models are considered in combination with different CME initiation models: magnetic foot point shearing and magnetic flux emergence. The simulations show that the initial magnetic polarity substantially affects the IP evolution of the CMEs influencing the propagation velocity, the shape, the trajectory (and, thus, the geo-effectiveness).

Summary:In this paper two new donor‐embedded polybinaphthalenes prepared by the Heck reaction are presented. By introducing a double bond in the polymer backbone, the supramolecular structure was altered in comparison with polymers without the double bond. Comparison between the CD/UV‐Vis spectra of polymers, with and without the double bond (previously synthesized in our laboratory) proved this change in a supramolecular structure. The double bonds also allow crosslinking upon heat treatment. NLO experiments demonstrated a more stable nonlinearity over time depending on the degree of crosslinking.

Muscle function depends on an adequate ATP supply to sustain the energy consumption associated with Ca(2+) cycling and actomyosin sliding during contraction. In this regulation of energy homeostasis, the creatine kinase (CK) circuit for high energy phosphoryl transfer between ATP and phosphocreatine plays an important role. We earlier established a functional connection between the activity of the CK system and Ca(2+) homeostasis during depolarization and contractile activity of muscle. Here, we show how CK activity is coupled to the kinetics of spontaneous and electrically induced Ca(2+) transients in the sarcoplasm of myotubes. Using the UV ratiometric Ca(2+) probe Indo-1 and video-rate confocal microscopy in CK-proficient and -deficient cultured cells, we found that spontaneous and electrically induced transients were dependent on ryanodine-sensitive Ca(2+) release channels, sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase pumps, extracellular calcium, and functional mitochondria in both cell types. However, at increasing sarcoplasmic Ca(2+) load (induced by electrical stimulation at 0.1, 1, and 10 Hz), the Ca(2+) removal rate and the amount of Ca(2+) released per transient were gradually reduced in CK-deficient (but not wild-type) myotubes. We conclude that the CK/phosphocreatine circuit is essential for efficient delivery of ATP to the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase pumps and thereby directly influences sarcoplasmic reticulum refilling and the kinetics of the sarcoplasmic Ca(2+) signals.

We have studied the mechanisms that regulate the remodeling of the glycolytic, mitochondrial and structural network of muscles of creatine kinase M (M‐CK)/sarcomeric mitochondrial creatine kinase (ScCKmit) knockout mice by comparison of wild‐type and mutant mRNA profiles on cDNA arrays. The magnitudes of changes in mRNA levels were most prominent in M‐CK/ScCKmit (CK−/−) double mutants but did never exceed those of previously observed changes in protein level for any protein examined. In gastrocnemius of CK−/−mice we measured a 2.5‐fold increase in mRNA level for mitochondrial encoded cytochrome coxidase (COX)‐III which corresponds to the increase in protein content. The level of the nuclear encoded mRNAs for COX‐IV, H+‐ATP synthase‐C, adenine nucleotide translocator‐1 and insulin‐regulatable glucose transporter‐4 showed a 1.5‐fold increase, also in agreement with protein data. In contrast, no concomitant up‐regulation in mRNA and protein content was detected for the mitochondrial inorganic phosphate‐carrier, voltage‐dependent anion channel and certain glycolytic enzymes. Our results reveal that regulation of transcript level plays an important role, but it is not the only principle involved in the remodeling of mitochondrial and cytosolic design of CK−/−muscles.

Skeletal muscles respond with high plasticity to pathobiological conditions or changes in physiological demand by remodeling cytoarchitectural and metabolic characteristics of individual myocytes. We have previously shown that muscles of mice without mitochondrial and/or cytosolic creatine kinases (ScCKmit−/−and/or M‐CK−/−) partly compensate for the defect(s) by redirecting metabolic pathways and ultrastructural characteristics. Here, we show by semiquantitative Western blot analysis that the compensatory changes involve mutation‐ and fiber‐type–specific coordinated regulation of divergent but functionally coupled groups of proteins. Fast‐twitch gastrocnemius muscle of CK−−/−−mice display a two‐ to fourfold upregulation of mitochondrial cytochrome coxidase, inorganic phosphate carrier, adenine nucleotide translocator, and voltage‐dependent anion channel proteins. In parallel, cytosolic myoglobin is upregulated. Slow‐twitch soleus muscle responds with changes in the glycolytic enzyme pattern, including a shift in lactate dehydrogenase isoenzyme composition. Adaptations in the network for oxidative adenosine triphosphate (ATP) production are already apparent at 17 days of age. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 1188–1196, 2001