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To develop health promotion (HP) in sports clubs (SCs), stakeholders need to know the HP expectations of sports participants. However, the literature does not provide information on these aspects, which exacerbates the difficulty for SCs to provide an environment, activities and organization that promote health and to play the role entrusted to them in the integration of vulnerable populations. To fill this gap, this study explores the HP expectations and perceptions of sports participants, with a particular focus on ethnocultural characteristics, and documents participants' understanding of HP. A descriptive qualitative study comprising semi-structured interviews was carried out with 22 French and Quebec sports participants. Because they have little experience with HP in their SC, participants do not seem to have many expectations of their SC in terms of HP. Nevertheless, they felt that SCs can play an important role in health and suggested several themes and types of action, such as seminars on nutrition, activities outside the SC to develop cohesion or health monitoring. Sports participants from ethnocultural minorities seem to appreciate the programs designed to integrate them. There is a predominantly physical conception of health and the contribution of SCs to health, and the relationship between the types of health determinants (economic, environmental, organizational and social) and health is not clear. This study shows that the idea of a health-promoting SC appeals to SC participants, but this approach has not yet taken root in this setting or in society as a whole., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

This systematic review aimed to provide an overview of test protocols used to measure peak oxygen uptake (VO 2 peak) in adults with Down syndrome (DS) and to determine how generalisable the outcomes are for the entire population of adults with DS by describing the sample characteristics of these studies and their impact on VO 2 peak. A literature search (PROSPERO CRD42022309560) was performed (18 July 2023) using the following databases: PubMed, CINAHL, APA PsycINFO, Web of Science, Embase and SPORTDiscus. For articles to be included, they had to be peer-reviewed pubications, reporting VO 2 peak or VO 2 max for individuals with DS separately, with a sample of n ≥ 5 and a mean age ≥18 years. Systematic reviews and meta-analyses were excluded but their reference lists were searched for additional papers to include. Studies were evaluated for risk of bias following the guidelines of Kmet et al. The results were summarised with frequency statistics. Forty-three studies were included in this systematic review. Sample sizes of included adults with DS ranged from n = 4-226, with a total of n = 1498 adults with DS being included. Most studies (29/43) used the same standardised maximal exercise treadmill protocol to measure VO 2 peak in adults with DS, and 33 out of 43 studies used at least one objective criterion to determine a valid maximal effort. Participants were predominantly male, under 40 years old, and overweight or obese. Additionally, the diversity of study samples was lacking or not reported. The most widely used, standardised, maximal exercise test treadmill protocol is recommended for future use in research and practice, including objective criteria to determine valid maximal effort. The current study samples are not representative of the population of adults with DS in terms of sex, age and diverse backgrounds and therefore likely overestimate VO 2 peak of this population., (© 2024 The Authors. Journal of Intellectual Disability Research published by John Wiley & Sons and MENCAP.)

Revascularization via coronary artery bypass grafting (CABG) to treat cardiovascular disease is established as one of the most important lifesaving surgical techniques worldwide. But the shortage in functionally self-adaptive autologous arteries leads to circumstances where the clinical reality must deal with fighting pathologies coming from the mismatching biophysical functionality of more available venous grafts. Synthetic biomaterial-based CABG grafts did not make it to the market yet, what is mostly due to technical hurdles in matching biophysical properties to the complex demands of the CABG niche. But bacterial Nanocellulose (BNC) Hydrogels derived by growing biofilms hold a naturally integrative character in function-giving properties by its freedom in designing form and intrinsic fiber architecture. In this study we use this integral to combine impacts on the luminal fiber matrix, biomechanical properties and the reciprocal stimulation of microtopography and induced flow patterns, to investigate biomimetic and artificial designs on their bio-functional effects. Therefore, we produced tubular BNC-hydrogels at distinctive designs, characterized the structural and biomechanical properties and subjected them to in vitro endothelial colonization in bioreactor assisted perfusion cultivation. Results showed clearly improved functional properties and gave an indication of successfully realized stimulation by artery-typical helical flow patterns., (© 2023. Springer Nature Limited.)

Objective: Prenatal tracheal occlusion (TO) promotes lung growth and is applied clinically in fetuses with congenital diaphragmatic hernia (CDH). Limited data are available regarding the effect of duration versus timepoint of TO. Our objective was to document the impact of TO on lung development in the near-term period in rats with nitrofen-induced CDH., Method: Nitrofen was administered on embryonic day (ED)9 and fetal TO was performed on ED18.5, 19, or 20 (term = ED22). Sham-operated and untouched littermates served as controls. Lungs were harvested in 0.5-day steps and only fetuses with a left-sided CDH were included in further analyses. Healthy fetuses provided a reference for normal near-term lung development., Results: Duration of TO in the nitrofen rat model for CDH predicts lung growth in terms of lung-body-weight ratio as well as an increased mRNA level of the proliferation marker Ki67. Longer TO also induced a more complex airway architecture. The timepoint of TO was not predictive of lung growth., Conclusion: In the nitrofen rat model of CDH, a longer period of TO leads to enhanced lung growth and more refined airway architecture., (© 2023 John Wiley & Sons Ltd.)

Background: Individuals with Down syndrome (DS) have low levels of cardiorespiratory fitness and previous studies have shown that these low levels of fitness have a physiological cause. During exercise, the cardiovascular, ventilatory and muscular systems are simultaneously active. While individual parameters of these systems have been investigated in DS before, the interaction between these parameters and systems have not been discussed in detail. Doing so may provide important insight regarding the aetiology of low cardiorespiratory fitness and which parameters of the cardiovascular, pulmonary and muscular systems are altered in individuals with DS compared with their peers without DS., Methods: Cardiopulmonary exercise tests were performed in healthy adults with and without DS. Parameters related to the cardiovascular, ventilatory and muscular systems were collected until VO 2peak . In total, 51 participants were included in analysis, of which 21 had DS., Results: Individuals with DS showed lower peak values for all collected outcomes (P ≤ 0.001) compared with those without DS, except for ventilatory threshold as a percentage of maximal oxygen uptake and V E /VCO 2 slope, which were similar., Conclusions: Our results show that individuals with DS present impairments across the cardiovascular, ventilatory and muscular aspects of the cardiopulmonary system., (© 2022 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.)

Objective: This study considers the example of one council who deliberately implemented menopause considerations into their well-being strategy instead of instituting a menopause policy. This example is used to explore whether such a strategy is a more viable and effective alternative., Study Design: An online survey was distributed amongst council workers and completed by 189 individuals. The questions covered respondents' own experiences of menopause transition at work (where applicable) and the availability of information and support for menopause at work, as well as a range of contextual factors., Main Outcome Measures: Experiences of workplace environments and relationships by those experiencing menopause., Results: Results on menopause experiences in this council are comparable to those in organizations who have implemented menopause policies or guidelines. Contextual factors, including gendered vertical segregation and racism, are highlighted as important factors influencing the experience of menopause transition in the workplace., Conclusions: Early indications suggest that integrating menopause support into a health and well-being strategy helps mainstream menopause issues amongst staff. Long-term assessment is required to consider whether it is more effective than introducing a menopause policy or guidelines.

Urethral strictures most frequently affect the bulbar but are also observed in the penile, glandular, or membranous urethra. They are often iatrogenic. Radiologic diagnosis can be established easily and safely by cystourethrography. Simple Sachse urethrotomy can result in permanent relief in the case of short bulbar strictures in initial findings. Recurrent structures or strictures in other locations should however be treated by open surgery, as cure cannot be achieved by other means. Depending on the diagnosis and comorbidities, end-to-end anastomosis, graft/flap urethroplasty, or perineal urethrostomy can be performed. If open surgery is delayed, aggravation of the diagnosis and worsening of the prognosis can be expected, regardless of the applied treatment., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Cardiorespiratory fitness, expressed as peak oxygen uptake during exercise (VO 2 peak), is an important predictor of cardiovascular health and is related to anthropometry in the general population. Individuals with Down syndrome (DS) have reduced cardiorespiratory fitness and often exhibit different anthropometrics compared with the general population. Interestingly, the relation between anthropometry and cardiorespiratory fitness found in the general population is not apparent in individuals with DS. However, accurate measures with dual energy X-ray absorptiometry (DEXA) scan have not been used to investigate this relationship in this population. The purpose of this paper was to investigate the relationship between accurate measures of anthropometry and cardiorespiratory fitness in adults with DS compared with an age-matched and sex-matched control group., Methods: Anthropometrics (height, weight, waist and hip circumference, body composition via DEXA) and cardiorespiratory fitness (VO 2 peak, measured during a graded maximal exercise test) were assessed in adults with (n = 9; 25 ± 3 years; 6 male patients) and without DS (n = 10, 24 ± 4 years; 5 male patients)., Results: Participants with DS were shorter (P < 0.01) than without DS and had a higher body mass index (P < 0.01), waist circumference (WC) (P = 0.026) and waist/height ratio (WHtR) (P < 0.01), but similar weight, body surface area (BSA), waist/hip ratio and body composition (P > 0.05). Participants with DS had significantly lower relative VO 2 peak and VO 2 peak corrected for total lean mass (TLM), but similar absolute VO 2 peak, compared with without DS. In participants with DS, only WC and WHtR were associated with VO 2 peak, whereas in participants without DS, height, weight, BSA, TLM, leg lean mass and body fat percentage were associated with VO 2 peak., Conclusions: These results suggest that the relation between anthropometry and cardiorespiratory fitness found in the general population is not the same in adults with DS and that anthropometrics do not fully explain cardiorespiratory fitness in adults with DS. Further research into potential alternative explanations is required., (© 2021 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.)

The goal of this study was to investigate whether the sexual objectification and virtual violence against females in video games increases negative attitudes toward females, when addressing a variety of noted methodological issues. Study participants were randomly assigned to a control group, where participants played Madden NFL 12, or an experimental group, where participants played Grand Theft Auto. In the experimental group, participants played the game with a confederate, who exposed participants to sexual objectification and violence against females. Study results indicated that both the experimental and control groups had equivalently low levels of rape myth acceptance prior to game play. Immediately after game play, there still was no statistically significant difference in rape myth acceptance between groups; however, there was a decrease in rape myth acceptance for the experimental group. The decrease in rape myth acceptance continued and magnified for the experimental group, over time, to the point of creating a statistically significant difference between the two groups for the follow-up measure at the end of the study.

Genetic knock-in using homology-directed repair is an inefficient process, requiring the selection of few modified cells and hindering its application to primary cells. Here, we describe Homology independent gene Tagging (HiTag), a method to tag a protein of interest by CRISPR in up to 66% of transfected cells with one single electroporation. The technique has proven effective in various cell types and can be used to knock in a fluorescent protein for live cell imaging, to modify the cellular location of a target protein and to monitor the levels of a protein of interest by a luciferase assay in primary cells.

Purpose: To report a single surgeon experience with one year follow-up after open ureteroplasty with buccal mucosa graft (OUBMG) in the rare situation of long segment proximal ureteral strictures., Materials and Methods: Four patients with long segment proximal ureteral stricture underwent OU-BMG between February and July 2017. Functional outcome was assessed by pre- and postoperative serum creatinine, ultrasound and renal scintigraphy as well as patient reported outcomes., Results: Four patients with an average stricture length of 4 cm underwent OU-BMG between February and July 2017. No major postoperative complications occurred. Retrograde uretero-pyelography 6 weeks postoperatively revealed a watertight anastomosis followed by immediate emptying of the renal pelvis and ureter in all four patients. Ureteroscopy at this time showed a wide lumen with well-vascularized pink mucosa. After a mean follow-up time of 12.5 (12-14) months, postoperative serum creatinine was unimpaired. Renal scintigraphy revealed no signs of renal obstruction. With regard to intraoral surgery, no difficulties with mouth opening or intraoral dryness or numbness were reported., Conclusions: For patients with long segment ureteral strictures OU-BMG is a safe technique with excellent surgical and functional outcomes. Hence, the application of this technique should be encouraged and regarded as one of the standard options in case of this rare problem., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose., (© The Korean Urological Association, 2020.)

Objectives: This study explored experiences of, attitudes to, and knowledge about menopause in the workplace among participants from the UK to assess the extent to which menopause remains a taboo in this context. Method: An online survey was distributed via Trades Union Congress, UK networks and social media, and was completed by 5399 respondents. Questions explored three key issues relating to menopause at work: respondents' own experiences of menopause transition; disclosure at work; and availability of information on menopause at work. Result: The largest group (43.4%) of respondents were perimenopausal and 16.8% were postmenopausal; 12.3% indicated that they might be experiencing menopause but were not sure. Only 45.8% had disclosed their menopause status at work. Fewer than 20% were provided with information about menopause in their workplace but the majority would like such information to be available. Conclusion: The survey findings suggest some progress has been made to raise awareness about menopause in the workplace but that substantial work remains to be done to ensure women transitioning through menopause are supported.

The gut-pancreas axis plays a key role in the regulation of glucose homeostasis and may be therapeutically exploited to treat not only type 2 diabetes but also hypoglycemia and hyperinsulinemia. We identify a novel enteroendocrine cell type expressing the peptide hormone urotensin 2B (UTS2B). UTS2B inhibits glucagon-like peptide-1 (GLP-1) secretion in mouse intestinal crypts and organoids, not by signaling through its cognate receptor UTS2R but through the activation of the somatostatin receptor (SSTR) 5. Circulating UTS2B concentrations in mice are physiologically regulated during starvation, further linking this peptide hormone to metabolism. Furthermore, administration of UTS2B to starved mice demonstrates that it is capable of regulating blood glucose and plasma concentrations of GLP-1 and insulin in vivo. Altogether, our results identify a novel cellular source of UTS2B in the gut, which acts in a paracrine manner to regulate GLP-1 secretion through SSTR5. These findings uncover a fine-tuning mechanism mediated by a ligand-receptor pair in the regulation of gut hormone secretion, which can potentially be exploited to correct metabolic unbalance caused by overactivation of the gut-pancreas axis., (Copyright © 2019 Endocrine Society.)

Purpose: To investigate changes in clinical data and pathological features of prostatectomy specimens of prostate cancer (PCa) patients in a large tertiary care center over the last 12 years as potential consequence of reduced acceptance of prostate-specific antigen (PSA)-based screening and implementation of active surveillance as a therapeutic option in PCa., Methods: We retrospectively identified all patients with PCa who underwent radical prostatectomy at our institution between 2004 and 2016 from our clinical database. We reviewed clinical and pathological data including patient age, PSA level, number of positive cores and Gleason score in prostate biopsy, and pathologic N- and T-stage, and Gleason score in radical prostatectomy specimen., Results: Data of 5497 consecutive patients were analyzed. Median PSA increased from 7 (IQR 4.8-10.5) to 9 ng/ml (IQR 5.8-16.1; p < 0.001), and median number of positive biopsy cores increased from 3 (IQR 2-5) to 5 (IQR 3-7; p < 0.001). The proportion of patients with Gleason score ≥ 7 in biopsy and prostatectomy specimens increased from 40 to 78% and 49 to 89% (p < 0.001), respectively. The rate of locally advanced (≥ pT3a) and lymph node-positive tumors increased from 28 to 43% and 5 to 16% (p < 0.001), respectively., Conclusions: We observed a significant change in clinical and pathological findings in our prostatectomy series with a significantly higher proportion of aggressive and locally advanced PCa in recent years. These findings may be related to a reduced acceptance of PSA-based screening and the use of active surveillance as management strategy and have significant impact on daily patient care.

Ureteral injuries account for less than 3% of genitourinary injuries. Most of them are caused iatrogenically during abdominal surgery. The symptoms are often non-specific and do not aid in diagnosis. The later the injury is detected, the more often complications occur. Therefore, in such situations it is important to consider the possibility of ureteral injury and initiate further diagnostic steps as soon as possible. A variety of diagnostic tests are available. In addition to the direct inspection of the ureters and retrograde ureteropyelography, computed tomography (CT) urography is routinely used. Based on the time of diagnosis as well as the extent and the localization of the injury, the further procedure can be determined. For minor injuries, the insertion of a ureteral splint is usually the treatment of choice. In the case of higher grade damage, operative reconstruction by one of several possible surgical procedures is indicated.

Purpose: Like in many other joints, current shoulder replacement designs aim at bone preservation. According to the literature available, stemless total shoulder arthroplasty (TSA) compares favourably with stemmed designs in terms of function and survivorship of the implant. However, long-term results of stemless shoulder arthroplasty are still missing. Therefore, the aim of the present study was to evaluate long-term results of stemless anatomical TSA., Methods: Between 2006 and 2009, 51 shoulders in 46 patients were resurfaced using the Biomet Total Evolutive Shoulder System (TESS). Thirty-one shoulders in 26 patients who were aged 66.7 ± 10.0 (range 34-82) years were available for review at a mean follow-up of 94.7 ± 11.3 (76-124) months., Results: The implant survival rate was 93.5% at eight years. The overall revision rate of the TESS implant was 9.7%. Radiolucent lines were found on the glenoid side of the TESS arthroplasty in 90.9% of the cases. All stemless humeral corolla implants showed solid fixation at follow-up. Clinical scores significantly improved at long-term follow-up (VAS from 8.1 ± 0.9 to 1.0 ± 1.2, p < 0.001; Quick-DASH from 67.9 ± 13.5 to 18.7 ± 16.5, p < 0.001 and Constant score from 14.7 ± 6.1 to 68.8 ± 13.2, p < 0.001)., Conclusions: Stemless TSA has stood the test of time at eight years in terms of clinical scores, radiographic loosening, complication rates and implant survivorship.

Urethral stricture is a narrowing of the urethra due to scar tissue. It causes obstructive voiding dysfunction and can lead to long-term damage of the entire urinary tract. The probability of therapeutic success is dampened by a high rate of recurrence. Therefore, a careful taking of the patient's history and further diagnostics are crucial for finding the appropriate form of therapy. This review highlights the clinical presentation and diagnostic workup of urethral strictures.

Background: The development of a stricture of the vesicourethral anastomosis is a serious complication after radical prostatectomy. Strictures occur in 5-8% of patients after radical prostatectomy., Symptoms: Usually the clinical symptoms include an irritative and obstructive component similar to benign prostatic hyperplasia. In rare cases, patients suffer from partial or complete stress incontinence as a result of the anastomotic stricture., Diagnostics: The diagnostic workup is similar to the procedure for urethral strictures. In addition to uroflowmetry, a cystourethrogram (CUG) or, if necessary, a micturating cystourethrogram (MCU) can be performed. A urethrocystoscopy can be performed to ensure the diagnosis., Therapy: In most cases, endoscopic procedures were performed for treatment. Beside a transurethral dilation of the stricture or the Sachse urethrotomy, the most common procedure is transurethral resection to treat the stricture. However, all procedures are associated with a high recurrence rate. In recurrent strictures, open surgical procedures, usually a perineal reanastomosis, should performed early., Conclusion: Endourological procedures like transurethral resection are a good treatment option, but due to the high recurrence rates, open surgical procedures should be discussed and if necessary should be performed early.

GPR15 is an orphan G protein-coupled receptor (GPCR) that is found in lymphocytes. It functions as a co-receptor of simian immunodeficiency virus and HIV-2 and plays a role in the trafficking of T cells to the lamina propria in the colon and to the skin. We describe the purification from porcine colonic tissue extracts of an agonistic ligand for GPR15 and its functional characterization. In humans, this ligand, which we named GPR15L, is encoded by the gene C10ORF99 and has some features similar to the CC family of chemokines. GPR15L was found in some human and mouse epithelia exposed to the environment, such as the colon and skin. In humans, GPR15L was also abundant in the cervix. In skin, GPR15L was readily detected after immunologic challenge and in human disease, for example, in psoriatic lesions. Allotransplantation of skin from Gpr15l -deficient mice onto wild-type mice resulted in substantial graft protection, suggesting nonredundant roles for GPR15 and GPR15L in the generation of effector T cell responses. Together, these data identify a receptor-ligand pair that is required for immune homeostasis at epithelia and whose modulation may represent an alternative approach to treating conditions affecting the skin such as psoriasis., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Before making a treatment decision for patients presenting with a urethral stricture, following anamnesis and general examinations, appropriate diagnostics are necessary. This includes at least uroflowmetry and cystourethrography and the use of ultrasound and cystoscopy may be of additional help. The curative treatment of a urethral stricture is always an operation. Besides endourological procedures, open surgery for urethral reconstruction is also performed. This article aims to give an overview about the necessary diagnostic measures and the pros and cons of the different operative therapies.

Background: Krabbe disease (KD) is an inherited leukodystrophy due to a defect in the GALC gene which encodes the lysosomal galactosylceramide β-galactosidase (GALC). About two thirds of patients show the early onset form of KD dominated by cerebral demyelination leading to death in early infancy. Late onset forms include a spectrum of late infantile, juvenile and adult clinical courses. The deficiency of GALC leads to a galactosylceramide lipidosis in which lysosomal storage phenomena are seen almost only at the ultrastructural level., Results: In a 4-year-old boy, the clinical suspicion of KD was high according to neurologic and neuroimaging findings. However, laboratory results were inconclusive; white blood cell GALC activity being at 23 to 25% of the normal level, and GALC genotyping revealing the new homozygous p.Ala543Pro variant which, ex silico, was of unclear significance. Studying a skin biopsy, cultured fibroblasts showed the GALC activity at 21 to 30% of the normal level; ultrastructurally, clearly KD-specific inclusions were seen in the eccrine sweat gland cells, confirming a KD diagnosis., Conclusion: The high clinical suspicion combined with the morphologic evidence for KD predict that the p.Ala543Pro variant is pathogenic for (late onset) KD. A hypothesis linked to the proline in the mutant GALC may explain the in vitro effect with high residual GALC activity. This patient would not have been correctly diagnosed, despite the strong clinical criteria of KD, if the electron microscopic results had not been available. The detailed knowledge of neurologic and neuroimaging signs is important in diagnostically problematic KD patients in which also an electron microscopic approach can be crucial., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Study Objective: This trial aimed to compare postoperative analgesia, opioid consumption, duration of ileus and hospital stay, and cytokine levels in patients undergoing laparoscopic cholecystectomies who received intravenous lidocaine in comparison with a control group., Design: Prospective, longitudinal, double-blind, and randomized study., Setting: Operating room and postoperative recovery area., Patients: Forty-four American Society of Anesthesiologists I and II patients older than 17 years, undergoing laparoscopic cholecystectomy, under general anesthesia., Interventions: The first group received intravenous lidocaine during the procedure until 1 hour postoperatively, whereas the second group received saline. Both groups received dipyrone and morphine patient-controlled analgesia., Measurements: Pain was assessed by Visual Numeric Scale at rest and when coughing at different times after the end of the surgery. Blood samples were taken at the end of procedure and 24 hours later. The total morphine patient-controlled analgesia demand, the time for the first flatus, and the length of hospital stay were also recorded., Main Results: Groups were similar in relation to sex (P= .2), age (P= .5), weight (P= .08), and length of surgery (P= .6). No differences were observed regarding the intensity of postoperative pain between the groups, either at rest (P= .76) or when coughing (P= .31), in morphine consumption (P= .9), and in the duration of ileus (P= .5) or length of hospital stay (P= .9). The inflammatory markers interleukin (IL)-1 (P= .02), IL-6 (P< .01), interferon-γ (P< .01), and tumor necrosis factor α (P< .01) showed significant reduction in the lidocaine group against the placebo group, except IL-10 (P= .01), that, because of its anti-inflammatory effects, increased its concentration., Conclusions: Intravenous lidocaine was not able to reduce postoperative pain, opioid consumption, and duration of ileus or length of hospital stay. However, its anti-inflammatory effect was noticeable., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Urinary tract infections are among the most common bacterial infectious diseases worldwide. Every second woman will experience at least one urinary tract infection in her lifetime. The administration of antibiotics has been a safe and efficient treatment modality so far. However, due to the emergence of multi-resistant pathogens and the developmental void of new antimicrobial drugs, the therapy of infections mighty become more challenging in the near future. So, knowledge of the complex host-pathogen interaction is of great importance. Common phenotypes observed in clinical practice suggest basic principles, which are relevant for the development of novel antimicrobial strategies. With invading pathogens forming intracellular bacterial communities they evade host response and provide a nidus for recurrent infection. A plethora of virulence factors allow uropathogenic bacteria to colonize and to establish infections in the urinary tract. In response, host responses seem to address specific virulence mechanisms that are essential to pathogenicity. Deciphering the molecular mechanisms underlying the complex host-pathogen interaction is critical to devise novel treatment options., (© Georg Thieme Verlag KG Stuttgart · New York.)

Lung hypoplasia in congenital diaphragmatic hernia (CDH) is a life-threatening birth defect. Severe cases can be offered tracheal occlusion to boost prenatal lung development, although defining those to benefit remains challenging. Metabonomics of (1)H NMR spectra collected from amniotic fluid (AF) can identify general changes in diseased versus healthy fetuses. AF embodies lung secretions and hence might contain pulmonary next to general markers of disease in CDH fetuses. AF from 81 healthy and 22 CDH fetuses was collected. NMR spectroscopy was performed at 400 MHz to compare AF from fetuses with CDH against controls. Several advanced feature extraction methods based on statistical tests that explore spectral variability, similarity, and dissimilarity were applied and compared. This resulted in the identification of 30 spectral regions, which accounted for 80% variability between CDH and controls. Combination with automated classification discriminates AF from CDH versus healthy fetuses with up to 92% accuracy. Within the identified spectral regions, isoleucine, leucine, valine, pyruvate, GABA, glutamate, glutamine, citrate, creatine, creatinine, taurine, and glucose were the most concentrated metabolites. As the metabolite pattern of AF changes with fetal development, we have excluded metabolites with a high age-related variability and repeated the analysis with 12 spectral regions, which has resulted in similar classification accuracy. From this analysis, it was possible to distinguish between AF from CDH fetuses versus healthy controls independent of gestational age.

Introduction: Cancer patients generally have a great need for disease-related information. They prefer to be informed personally by the attending doctor. Yet, they also use other sources, mostly from medical laypersons or public media. The goal of our survey was to obtain insight into information patients get and their requirements regarding information., Methods and Participants: Using a standardized questionnaire, we conducted a survey on 226 patients and 32 relatives, who attended meetings providing information for cancer patients., Results: Patients were generally content or highly content with the information they got. The direct consultation with the doctor is the most important source of information especially for older patients. Information by other patients and self-help groups rank second, followed by internet and online chats, which both are of minor importance for patients older than 60 years. From the patients' point of view, sources of information should be individualized and comprehensive, provided by experts and allowing for questions. Patients prefer one constant person for communication. Remarkably, empathic communication was not rated as important. Age and gender are not associated with these preferences for these characteristics of sources of information., Discussion: Patients' and relatives' desire for an individualized, comprehensive counseling with high expertise provided by one person points to the limits of resources of the health system. The importance of additional information material will rise accordingly. This material should be tailored to the needs of diverse patient groups., (© Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Despite recent advances in the management of septic shock, mortality remains unacceptably high. Earlier initiation of key therapies including appropriate antimicrobials and fluid resuscitation appears to reduce the mortality in this condition. This study examined whether early initiation of vasopressor therapy is associated with improved survival in fluid therapy-refractory septic shock., Methods: Utilizing a well-established database, relevant information including duration of time to vasopressor administration following the initial documentation of recurrent/persistent hypotension associated with septic shock was assessed in 8,670 adult patients from 28 ICUs in Canada, the United States of America, and Saudi Arabia. The primary endpoint was survival to hospital discharge. Secondary endpoints were length of ICU and hospital stay as well as duration of ventilator support and vasopressor dependence. Analysis involved multivariate linear and logistic regression analysis., Results: In total, 8,640 patients met the definition of septic shock with time of vasopressor/inotropic initiation documented. Of these, 6,514 were suitable for analysis. The overall unadjusted hospital mortality rate was 53%. Independent mortality correlates included liver failure (odds ratio (OR) 3.46, 95% confidence interval (CI), 2.67 to 4.48), metastatic cancer (OR 1.63, CI, 1.32 to 2.01), AIDS (OR 1.91, CI, 1.29 to 2.49), hematologic malignancy (OR 1.88, CI, 1.46 to 2.41), neutropenia (OR 1.78, CI, 1.27 to 2.49) and chronic hypertension (OR 0.62 CI, 0.52 to 0.73). Delay of initiation of appropriate antimicrobial therapy (OR 1.07/hr, CI, 1.06 to 1.08), age (OR 1.03/yr, CI, 1.02 to 1.03), and Acute Physiology and Chronic Health Evaluation (APACHE) II Score (OR 1.11/point, CI, 1.10 to 1.12) were also found to be significant independent correlates of mortality. After adjustment, only a weak correlation between vasopressor delay and hospital mortality was found (adjusted OR 1.02/hr, 95% CI 1.01 to 1.03, P <0.001). This weak effect was entirely driven by the group of patients with the longest delays (>14.1 hours). There was no significant relationship of vasopressor initiation delay to duration of vasopressor therapy (P = 0.313) and only a trend to longer duration of ventilator support (P = 0.055) among survivors., Conclusion: Marked delays in initiation of vasopressor/inotropic therapy are associated with a small increase in mortality risk in patients with septic shock.

Historically, epilepsy has been ignored by the public health community, despite the fact that there are more than 2 million people with epilepsy in the United States. Although epilepsy affects 1 in 26 people during their lifetime, the general public lacks basic knowledge and holds misperceptions about epilepsy that contribute to its associated stigma. Consequently, people with epilepsy continue to fare poorly, with lower physical, mental, and social well-being. Recently, the 2012 Institute of Medicine (IOM) report Epilepsy Across the Spectrum: Promoting Health and Understanding inspired a new sense of enthusiasm in the epilepsy community that can serve as a catalyst to change public perceptions about epilepsy. To erase stigma, the IOM committee made recommendations in two areas: (a) informing the media and (b) coordinating public awareness. The committee also identified eight key messages about epilepsy that the public should know. Health promotion and education professionals can play a critical role in disseminating these messages to the general public in their local communities and supporting interventions and policies to change the face of epilepsy.

Hedgehog (Hh) signaling determines cell fate during development and can drive tumorigenesis. We performed a screen for new compounds that can impinge on Hh signaling downstream of Smoothened (Smo). A series of cyclohexyl-methyl aminopyrimidine chemotype compounds ('CMAPs') were identified that could block pathway signaling in a Smo-independent manner. In addition to inhibiting Hh signaling, the compounds generated inositol phosphates through an unknown GPCR. Correlation of GPCR mRNA expression levels with compound activity across cell lines suggested the target to be the orphan receptor GPR39. RNA interference or cDNA overexpression of GPR39 demonstrated that the receptor is necessary for compound activity. We propose a model in which CMAPs activate GPR39, which signals to the Gli transcription factors and blocks signaling. In addition to the discovery of GPR39 as a new target that impinges on Hh signaling, we report on small-molecule modulators of the receptor that will enable in vitro interrogation of GPR39 signaling in different cellular contexts.

Pain resulting from the application of orthodontic forces varies markedly across individuals. The reasons of this variability are still largely unknown. To investigate factors that may be associated with orthodontic pain following the application of orthodontic separators. One hundred and seven participants were screened for pain response over 48 h following placement of orthodontic elastomeric separators. The highest (n = 10) and lowest (n = 10) pain responders were identified, and data collected on tooth pain sensitivity to electrical stimulation in conjunction with using the Pain Catastrophising Scale (PCS), Dental Anxiety Scale (DAS) and cold pressor test (CPT). There were statistically significant differences between high- and low-pain responders in catastrophising score (P ≤ 0.023). For every PCS magnification score of 1 unit higher, the relative risk of being a high-pain responder was 1.6 (P = 0.002); those scoring higher on helplessness had a lower risk of being so. DAS scores of high-pain responders were twice as high as those of low-pain responder (P = 0.043). During the first 2 min of CPT, the high-pain responders experienced more pain than the low-pain responders (P ≤ 0.029). Tooth pain thresholds did not differ between the two different pain responder groups. Pain catastrophising, dental anxiety and cold sensitivity appear to modify the pain experienced following placement of orthodontic separators. Further research is needed to determine the validity of screening questions to identify at-risk patients prior to commencing orthodontic treatment., (© 2014 John Wiley & Sons Ltd.)

TLQP-21, a peptide derived from VGF (non-acronymic) by proteolytic processing, has been shown to modulate energy metabolism, differentiation, and cellular response to stress. Although extensively investigated, the receptor for this endogenous peptide has not previously been described. This study describes the use of a series of studies that show G protein-coupled receptor-mediated biological activity of TLQP-21 signaling in CHO-K1 cells. Unbiased genome-wide sequencing of the transcriptome from responsive CHO-K1 cells identified a prioritized list of possible G protein-coupled receptors bringing about this activity. Further experiments using a series of defined receptor antagonists and siRNAs led to the identification of complement C3a receptor-1 (C3AR1) as a target for TLQP-21 in rodents. We have not been able to demonstrate so far that this finding is translatable to the human receptor. Our results are in line with a large number of physiological observations in rodent models of food intake and metabolic control, where TLQP-21 shows activity. In addition, the sensitivity of TLQP-21 signaling to pertussis toxin is consistent with the known signaling pathway of C3AR1. The binding of TLQP-21 to C3AR1 not only has effects on signaling but also modulates cellular functions, as TLQP-21 was shown to have a role in directing migration of mouse RAW264.7 cells.

Background: The purpose was to evaluate the interventional effects of activity trails (courses) on fall risk factors and health-related quality of life (hrQoL)., Materials and Methods: A total of 94 subjects (67.7 ± 5.7 years; 29 men, 65 women) completed the following measurements prior to and 12 weeks after the initiation of the activity trail intervention: maximum isometric leg extensors force (Fmax, m3 diagnoses©), gait velocity (GV), and static postural stability (STAB, Zebris FDM©), fall-associated self-efficacy (FALL, FES-I), and hrQoL (SF-36)., Results: During the 12-week intervention period, the participants increased Fmax (1.63 ± 0.6 vs. 1.70 ± 0.6 N•kg(-1)) and GV (1.06 ± 0.25 vs. 1.11 ± 0.18m•s(-1); p < 0.05). Neither FALL (19.44 ± 3.6 vs. 19.41 ± 4.3 points) nor STAB (84.3 ± 56.4 vs. 79.7 ± 63.1 mm(2)) changed. Additionally, significant improvements in hrQoL regarding vitality (56.3 ± 17.2 vs. 63.2 ± 18.3 points) and mental health (69.4 ± 18.7 vs. 75.5 ± 16.5 points; p < 0.05) were found., Conclusion: The improvements in fall-related risk factors and hrQoL may be expected to contribute to fall prevention and psychosocial quality of life.

Objective: To explore the psychosocial impact of invasive fetal therapy (FT)., Methods: We studied 100 consecutive patients scheduled for invasive FT. Contemporary controls were women undergoing (1) invasive prenatal diagnosis (AC/CVS) and (2) first trimester risk assessment of aneuploidy (NT), and (3) women who declined the latter (CTR). Prior to the procedure, participants completed the Beck Depression Inventory II, the State-Trait Anxiety Inventory, the Dyadic Adjustment Scale and a questionnaire specifically designed to evaluate the process preceding the intervention., Results: Thirty-five percent of women in the FT group had mild to severe depressive symptoms, and 30% showed high levels of state anxiety. Mean state anxiety was significantly higher in women facing invasive as compared to non-invasive procedures. Trait anxiety levels and relationship scores were comparable across all groups. FT patients were more satisfied with the information and support given, whereas women in the NT group felt a greater degree of self-determination and contentedness with the choices they made., Conclusion: Pregnant women awaiting invasive prenatal diagnosis and FT face higher levels of state anxiety than women undergoing non-invasive procedures. Traits of depression and high state anxiety are found in at least one third of women undergoing FT., (© 2013 John Wiley & Sons, Ltd.)

Objectives: To determine whether malocclusion is associated with oral-health-related quality of life (OHRQoL) in New Zealand adolescents., Methods: Data from two cross-sectional epidemiological studies of adolescents in Taranaki and Otago were used. Each participant completed a self-administered questionnaire and underwent a clinical examination. Information collected included sociodemographic characteristics (sex, ethnicity and household deprivation), and clinical measures (caries and malocclusion, the latter measured with the Dental Aesthetic Index, or DAI). OHRQoL was measured using the validated 16-item impact short-form Child Perceptions Questionnaire (CPQ11-14). Linear regression was used to model the CPQ11-14 score., Results: 783 adolescents (52.6% male) took part. One-fifth had a handicapping malocclusion and one-third had a minor malocclusion or none. The overall mean DMFS was 2.3 (SD, 3.8), with slightly more than 50% being caries-free. With the exception of the oral symptoms domain, females presented with higher mean CPQ11-14 and domain scores, while Mãori had lower scores. There was a distinct gradient in mean CPQ11-14 and domain scores across the categories of malocclusion severity, whereby those in the 'handicapping' category of the DAI had the highest CPQ11-14 score. Linear regression modeling of the CPQ11-14 score showed that, after controlling for DMFS and socio-demographic characteristics, malocclusion category and being female were positively associated with higher CPQ11-14 scores., Conclusion: A severe malocclusion appears to have a negative impact on the OHRQoL of New Zealand adolescents.

In March 2012 the Institute of Medicine (IOM) released the report, Epilepsy Across The Spectrum: Promoting Health and Understanding. This report examined the public health dimensions of the epilepsies with a focus on the following four areas: public health surveillance and data collection and integration; population and public health research; health policy, health care, and human services; and education for providers, people with epilepsy and their families, and the public. The report provided recommendations and research priorities for future work in the field of epilepsy that relate to increasing the power of data on epilepsy; prevention of epilepsy; improving health care for people with epilepsy; improving health professional education about epilepsy; improving quality of life for people with epilepsy; improving education about epilepsy for people with epilepsy and families; and raising public awareness about epilepsy. For this article, the authors selected one research priority from each of the major chapter themes in the IOM report: expanding and improving the quality of epidemiologic surveillance in epilepsy; developing improved interventions for people with epilepsy and depression; expanding early identification/screening for learning impairments in children with epilepsy; evaluating and promoting effective innovative teaching strategies; accelerating research on the identification of risk factors and interventions that increase employment and improve quality of life for people with epilepsy and their families; assessing the information needs of people with epilepsy and their families associated with epilepsy-related risks, specifically sudden unexpected death in epilepsy; and developing and conducting surveys to capture trends in knowledge, awareness, attitudes, and beliefs about epilepsy over time and in specific population subgroups. For each research priority selected, examples of research are provided that will advance the field of epilepsy and improve the lives of people with epilepsy. The IOM report has many other research priorities for researchers to consider developing to advance the field of epilepsy and better the lives of people with epilepsy., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

The author describes from his personal involvement the many improvements to electron microscopy Albert Crewe and his group brought by minimizing the effects of aberrations. The Butler gun was developed to minimize aperture aberrations in a field emission electron gun. In the 1960s, Crewe anticipated using a spherical aberration corrector based on Scherzer's design. Since the tolerances could not be met mechanically, a method of moving the center of the octopoles electrically was developed by adding lower order multipole fields. Because the corrector was located about 15 cm ahead of the objective lens, combination aberrations would arise with the objective lens. This fifth order aberration would then limit the aperture of the microscope. The transformation of the off axis aberration coefficients of a round lens was developed and a means to cancel anisotropic coma was developed. A new method of generating negative spherical aberration was invented using the combination aberrations of hexapoles. Extensions of this technique to higher order aberrations were developed. An electrostatic electron mirror was invented, which allows the cancellation of primary spherical aberration and first order chromatic aberration. A reduction of chromatic aberration by two orders of magnitude was demonstrated using such a system., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The Wnt/β-catenin signaling pathbway controls many important biological processes. R-Spondin (RSPO) proteins are a family of secreted molecules that strongly potentiate Wnt/β-catenin signaling, however, the molecular mechanism of RSPO action is not yet fully understood. We performed an unbiased siRNA screen to identify molecules specifically required for RSPO, but not Wnt, induced β-catenin signaling. From this screen, we identified LGR4, then an orphan G protein-coupled receptor (GPCR), as the cognate receptor of RSPO. Depletion of LGR4 completely abolished RSPO-induced β-catenin signaling. The loss of LGR4 could be compensated by overexpression of LGR5, suggesting that LGR4 and LGR5 are functional homologs. We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5, and that overexpression of LGR4 strongly sensitizes cells to RSPO-activated β-catenin signaling. Supporting the physiological significance of RSPO-LGR4 interaction, Lgr4-/- crypt cultures failed to grow in RSPO-containing intestinal crypt culture medium. No coupling between LGR4 and heterotrimeric G proteins could be detected in RSPO-treated cells, suggesting that LGR4 mediates RSPO signaling through a novel mechanism. Identification of LGR4 and its relative LGR5, an adult stem cell marker, as the receptors of RSPO will facilitate the further characterization of these receptor/ligand pairs in regenerative medicine applications.

Objective: Iatrogenic preterm prelabor rupture of membranes (iPPROM; <37 weeks of gestation) is a major complication of fetal surgery. Little information is available about risk factors and incidence., Methods: We systematically reviewed reported iPPROM rates, gestational age at delivery and fetal survival after representative minimally invasive antenatal procedures., Results: A total of 1,146, 36 and 194 cases with mean iPPROM rates of 27, 31 and 26% were included for placental laser in twin-twin transfusion syndrome, shunting in lower urinary tract obstruction and interventions for twin-reversed arterial perfusion, respectively. In the statistical analysis, the maximum diameter of the instrument predicted iPPROM rate and was significantly related to gestational age at birth as well as fetal survival. Information on duration of the respective procedures was scarce and did not allow for meaningful analysis., Conclusions: iPPROM occurs in about 30% of cases treated by minimally invasive fetal surgery. The maximum diameter of the instrument explains iPPROM rate, gestational age at birth and fetal survival. Great variations in the reporting of iPPROM make data analysis difficult., (Copyright © 2011 S. Karger AG, Basel.)

Objective: Prenatal tracheal occlusion (TO) promotes lung growth and is applied clinically in fetuses with severe congenital diaphragmatic hernia. Limited data are available regarding the effect of duration of TO on lung development. Our objective was to evaluate the effects of long (2 and 2.5 days) versus short (1 day) TO on lung development in rats with nitrofen-induced diaphragmatic hernia., Method: Nitrofen was administered on embryonic day (ED) 9 and fetal TO performed either on ED18.5, 19 or 20 (term = 22 days). Sham-operated and untouched littermates served as controls. On ED21, lungs were harvested and only fetuses with a left-sided diaphragmatic defect were included in further analyses., Results: Lung-body-weight ratio incrementally increased with the duration of TO. Increased proliferation following long TO was confirmed by immunohistochemistry and qRT-PCR for the proliferation marker Ki-67. Irrespective of duration, TO induced more complex airway architecture. Medial wall thickness of pulmonary arteries was thinner after long rather than short TO., Conclusion: In the nitrofen rat model of congenital diaphragmatic hernia, a longer period of TO leads to enhanced lung growth and less muscularized pulmonary arteries., (© 2011 John Wiley & Sons, Ltd.)