Search

Purpose: The selection for either primary or interval cytoreductive surgery (CRS) in patients with epithelial ovarian cancer (EOC) is currently based on imaging techniques like computed tomography (CT), [ 18 F]fluorodeoxyglucose-positron emission tomography ([ 18 F]FDG-PET), diffusion-weighted magnetic resonance imaging (DW-MRI) and/or diagnostic laparoscopy, but these have limitations. Folate receptor (FR)-targeted PET/CT imaging, using [ 18 F]fluoro-PEG-folate, could improve preoperative assessment, potentially reducing unnecessary laparotomies. This paper presents the first experience with [ 18 F]fluoro-PEG-folate PET/CT imaging in advanced stage EOC, focusing on safety, tolerability, and feasibility for reflecting the extent of disease., Methods: Tolerability and safety were monitored after administration of the [ 18 F]fluoro-PEG-folate tracer by measurements of vital function parameters (blood pressure, heart rate, peripheral oxygen saturation, respiratory rate, and temperature). In addition, (serious) adverse events were recorded. Disease burden was quantified using the Peritoneal Cancer Index (PCI) score on preoperative [ 18 F]fluoro-PEG-folate PET/CT and during surgery. PCI scores were compared with intraoperative findings, considering histopathologic results as the gold standard. Tissue specimens were stained for FRα and FRβ. Relative uptake of the radiotracer by EOC lesions and other tissues was quantified using body weighted standardized uptake values (SUV)., Results: The study was terminated prematurely during the interim analysis after inclusion of eight patients of whom five had completed the study protocol. Although [ 18 F]fluoro-PEG-folate demonstrated safety, efficacy for tumor-specific imaging was limited. Despite clear FRα overexpression, low tracer uptake was observed in EOC lesions, contrasting with high uptake in healthy tissues, posing challenges in specificity and accurately assessing tumor burden., Conclusions: Overall, while [ 18 F]fluoro-PEG-folate was well-tolerated, its clinical utility in the preoperative assessment of the extent of disease in EOC was limited. This highlights the need for further research in developing targeted imaging agents for optimal detection of EOC metastases., Trial Registration: Clinicaltrials.gov, NCT05215496. Registered 31 January 2022., Competing Interests: Declaration of competing interest A.D. Windhorst is editor-in-chief of Nuclear Medicine & Biology and was not involved in the editorial review or the decision to publish this article. All other authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Extensive evidence is available on hormonal contraceptive (HC) use and the risk of a first venous thromboembolism (VTE) event. Despite recommendations to discontinue combined HC (CHC) use, some women continue or start its use after a first VTE., Objectives: We aimed to evaluate the VTE recurrence risk associated with HC use in premenopausal women., Methods: Premenopausal women with a first VTE included in the Multiple Environmental and Genetic Assessment of Venous Thrombosis study between 1999 and 2004 were followed for a recurrence until 2010. Data on HC use were available through linkage to the Dutch Foundation for Pharmaceutical Statistics. The risk of recurrence was assessed 1) during anticoagulant therapy and 2) after cessation of anticoagulant therapy. Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs adjusted for age and body mass index at baseline and thromboprophylaxis use during follow-up., Results: Six hundred fifty women were uniquely linked and followed for a total of 3538 person-years (median, 6.1 years), during which 57 VTE recurrences occurred. Five occurred (8.8%) during anticoagulation treatment, with no clear risk difference for CHC use vs nonuse (HR, 0.8; 95% CI, 0.1-8.2). After anticoagulation cessation, CHC use was associated with a 2.4-fold higher risk of recurrence (HR, 2.4; 95% CI, 1.2-5.0) compared with nonuse. Recurrence risk for levonorgestrel-releasing intrauterine device use was similar to that for nonuse (HR, 0.9; 95% CI, 0.3-3.1)., Conclusion: CHC use after a first VTE is safe during anticoagulant use but substantially increases the risk of a recurrent VTE event in absence of anticoagulant use. This study adds to the evidence regarding the use of a levonorgestrel-releasing intrauterine device as a safe alternative., Competing Interests: Declaration of competing interests The authors declare no competing interests. B.H.S. is currently employed at the Knowledge Institute of the Dutch Association of Medical Specialists, Utrecht, The Netherlands. J.F.T. is currently employed at ZonMw, The Hague, The Netherlands. L.E.F. is currently employed at Nivel, Utrecht, The Netherlands., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe the pharmacokinetic properties of the [ 18 F]fluoro-polyethylene glycol(PEG)-folate radiotracer in PET/CT imaging of patients with advanced stage epithelial ovarian cancer (EOC)., Procedures: In five patients with advanced EOC (FIGO stage IIIB/IIIC, Fédération Internationale de Gynécologie et d'Obstétrique), a 90-min dynamic PET acquisition of the pelvis was performed directly after i.v. administration of 185 MBq [ 18 F]fluoro-PEG 6 -folate. Arterial blood samples collected at nineteen timepoints were used to determine the plasma input function. A static volume of interest (VOI) for included tumor lesions was drawn manually on the PET images. Modelling was performed using PMOD software. Three different models (a 1-tissue compartment model (1T2k) and two 2-tissue compartment models, irreversible (2T3k) and reversible (2T4k)) were compared in goodness of fit with the time activity curves by means of the Akaike information criterion., Results: The pharmacokinetic analysis in the pelvic area has proven to be much more challenging than expected. Only four out of 22 tumor lesions in five patients were considered suitable to perform modelling on. The remaining tumor lesions were inapt due to either low tracer uptake, small size, proximity to other [ 18 F]fluoro-PEG 6 -folate -avid structures and/or displacement by abdominal organ motion in the dynamic scan. Data from the four analyzed tumor lesions suggest that the irreversible 2T3k may best describe the pharmacokinetics. All 22 lesions were immunohistochemically stained positive for the folate receptor alpha (FRα) after resection., Conclusion: Performing pharmacokinetic analysis in the abdominal pelvic region is very challenging. This brief article describes the challenges and pitfalls in pharmacokinetic analysis of a tracer with high physiological accumulation in the intestines, in case of lesions of limited size in the abdominal pelvic area., (© 2024. The Author(s).)

Anterior cruciate ligament (ACL) rupture is a frequently encountered injury among athletes, often requiring surgical intervention to restore knee stability. Magnetic resonance imaging (MRI) after ACL reconstruction is common, especially in the evaluation of clinical complications leading to knee instability, decreased range of motion, or pain. This article provides a detailed overview of normal and abnormal postoperative findings including a practical step-by-step guide for MRI assessment. MRI findings must be correlated with surgical technique, time interval from surgery to imaging, and clinical examination., Competing Interests: None declared., (Thieme. All rights reserved.)

Objectives: Deferred consent enables research to be conducted in the ICU when patients are unable to provide consent themselves, and there is insufficient time to obtain consent from surrogates before commencing (trial) treatment. The aim of this study was to evaluate how former ICU patients reflect on their participation in a study with deferred consent and examine whether their opinions are influenced by the quality of life (QoL) following hospital discharge., Design: Survey study by questionnaire., Setting: Eight ICUs in The Netherlands., Patients: Former ICU patients who participated in the ICONIC trial, a multicenter randomized clinical trial that evaluated oxygenation targets in mechanically ventilated ICU patients., Interventions: Participants enrolled in the ICONIC trial in one of the eight participating centers in The Netherlands received a questionnaire 6 months after randomization. The questionnaire included 12 close-ended questions on their opinion about the deferred consent procedure. QoL was measured using the EQ-5D-5L questionnaire. By calculating the EQ-5D index, patients were divided into four QoL quartiles, where Q1 reflects the lowest and Q4 is the highest., Measurements and Main Results: Of 362 participants who were contacted, 197 responded (54%). More than half of the respondents (59%) were unaware of their participation in the ICONIC study. In total 61% were content with the deferred consent procedure, 1% were not content, 25% neutral, 9% did not know, and 9% answered "other." Those with a higher QoL were more likely to be content ( p = 0.02). In all QoL groups, the legal representative was the most often preferred individual to provide consent., Conclusions: Former ICU patients who participated in the ICONIC study often did not remember their participation but were predominantly positive regarding the use of deferred consent. Those with a higher QoL were most likely to be content., Competing Interests: Dr. van der Wal’s institution received funding from the Dutch Research Council (NWO). Dr. Hemerhorst received support for article research from the NWO. Dr. Schultz is team leader of Medical Research at Hamilton Medical AG, Switzerland, since January 2022 and received grants from ZonMw, The Netherlands, for studies of ventilation. The Dutch Research Council funded the original trial, but was not involved in the study design, the collection of the data, the analysis or interpretation of the data, the writing of the report, or the decision to submit the article for publication. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Background: Most young children (0-3 years) attend formal childcare in Denmark, many of them fulltime. Yet recent reports of the quality of Danish childcare centers have shown that in more than one-third of nurseries, the interactions between caregivers and young children (0-3 years) are of "insufficient" quality, which constitutes a risk for affected children's well-being and development. Effective interventions to improve childcare providers' interactive skills are necessary., Methods: In this randomized controlled trial, we test the effectiveness of the Caregiver Interaction Profile training, which focuses on improving six core interactive skills: sensitive responsiveness, respecting children's autonomy, structuring and limit setting, verbal communication, developmental stimulation, and fostering positive peer interactions. We will recruit N = 200 childcare providers from nursery groups in Copenhagen (n = 100 training group, n = 100 waiting-list control group). Our primary outcomes are childcare providers' six interactive skills named above, observed from video-recorded interactions in the nursery groups. The secondary goal of our study is to test whether the training boosts children's social-emotional and linguistic development. To this end we aim to recruit N ≈ 500 children from participating childcare providers' nursery groups (n ≈ 250 training group, n ≈ 250 waiting-list control group). We measure social-emotional and linguistic development with various standardized questionnaires, filled out by parents and childcare providers., Discussion: If the training is effective at improving childcare providers' interactive skills, then this will be an important foundation for implementation efforts, such as offering the training as part of the educational program of childcare providers. Future research should also evaluate whether the Caregiver Interaction Profile training is effective for childcare providers of older children (3-5 years) in Danish kindergartens., Trial Registration: This trial is registered at clinicaltrials.gov as "Testing the Effects of the Caregiver Interaction Profile Training on the Interactive Skills of Daycare Providers (CDP)" with registry ID NCT05654116. Registration date: 12/01/2022., (© 2024. The Author(s).)

Purpose: The aim of the ESSKA 2022 consensus Part III was to develop patient-focused, contemporary, evidence-based, guidelines on the indications for revision anterior cruciate ligament surgery (ACLRev)., Methods: The RAND/UCLA Appropriateness Method (RAM) was used to provide recommendations on the appropriateness of surgical treatment versus conservative treatment in different clinical scenarios based on current scientific evidence in conjunction with expert opinion. A core panel defined the clinical scenarios with a moderator and then guided a panel of 17 voting experts through the RAM tasks. Through a two-step voting process, the panel established a consensus as to the appropriateness of ACLRev for each scenario based on a nine-point Likert scale (in which a score in the range 1-3 was considered 'inappropriate', 4-6 'uncertain', and 7-9 'appropriate')., Results: The criteria used to define the scenarios were: age (18-35 years vs 36-50 years vs 51-60 years), sports activity and expectation (Tegner 0-3 vs 4-6 vs 7-10), instability symptoms (yes vs no), meniscus status (functional vs repairable vs non-functional meniscus), and osteoarthritis (OA) (Kellgren-Lawrence [KL] grade 0-I-II vs grade III). Based on these variables, a set of 108 clinical scenarios was developed. ACLRev was considered appropriate in 58%, inappropriate in 12% (meaning conservative treatment is indicated), and uncertain in 30%. Experts considered ACLRev appropriate for patients with instability symptoms, aged ≤ 50 years, regardless of sports activity level, meniscus status, and OA grade. Results were much more controversial in patients without instability symptoms, while higher inappropriateness was related to scenarios with older age (51-60 years), low sporting expectation, non-functional meniscus, and knee OA (KL III)., Conclusion: This expert consensus establishes guidelines as to the appropriateness of ACLRev based on defined criteria and provides a useful reference for clinical practice in determining treatment indications., Level of Evidence: II., (© 2023. The Author(s).)

Research indicates increases in coercive parenting towards children and increases in child externalizing behavior during COVID-19 as compared to the pre-pandemic period. In this preregistered study, we extended previous knowledge by investigating to what extent, and under what conditions, changes in coercive parenting and child externalizing behavior are interrelated. Ninety-five mothers and fathers of children (of age 3 prior to the pandemic) reported on coercive parenting and child externalizing behavior before and during the pandemic, and trained assistants observed the quality of mother-child and father-child attachment relationship prior to the pandemic. We employed latent change score modeling to test the extent to which changes in maternal and paternal coercive parenting and changes in child externalizing behavior across the pre-pandemic period and the onset of the first COVID-19 lockdown are interrelated. Moreover, we tested whether these linkages are moderated by changes in the other parent's coercive parenting and the quality of parent-child attachment relationship. Specifically, we tested the moderation by mother-child (father-child) attachment relationship quality in the relation between changes in mothers' (fathers') coercive parenting and changes in child externalizing behavior. We found that changes in mothers', but not fathers' coercive parenting were positively associated with changes in child externalizing behavior. We found no moderation by changes in the other parent's parenting or by parent-child attachment relationship quality. Our findings provide support for the transactional processes underlying mothers' and children's behavior in the context of non-normative stressful conditions. We recommend incorporating evidence-based (parenting) support for mothers, fathers, and young children in prevention strategies and recovery tools employed during and after future lockdowns and non-normative stressful events., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hogye et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Rationale: Supplemental oxygen is widely administered to ICU patients, but appropriate oxygenation targets remain unclear. Objectives: This study aimed to determine whether a low-oxygenation strategy would lower 28-day mortality compared with a high-oxygenation strategy. Methods: This randomized multicenter trial included mechanically ventilated ICU patients with an expected ventilation duration of at least 24 hours. Patients were randomized 1:1 to a low-oxygenation (Pa O 2 , 55-80 mm Hg; or oxygen saturation as measured by pulse oximetry, 91-94%) or high-oxygenation (Pa O 2 , 110-150 mm Hg; or oxygen saturation as measured by pulse oximetry, 96-100%) target until ICU discharge or 28 days after randomization, whichever came first. The primary outcome was 28-day mortality. The study was stopped prematurely because of the COVID-19 pandemic when 664 of the planned 1,512 patients were included. Measurements and Main Results: Between November 2018 and November 2021, a total of 664 patients were included in the trial: 335 in the low-oxygenation group and 329 in the high-oxygenation group. The median achieved Pa O 2 was 75 mm Hg (interquartile range, 70-84) and 115 mm Hg (interquartile range, 100-129) in the low- and high-oxygenation groups, respectively. At Day 28, 129 (38.5%) and 114 (34.7%) patients had died in the low- and high-oxygenation groups, respectively (risk ratio, 1.11; 95% confidence interval, 0.9-1.4; P  = 0.30). At least one serious adverse event was reported in 12 (3.6%) and 17 (5.2%) patients in the low- and high-oxygenation groups, respectively. Conclusions: Among mechanically ventilated ICU patients with an expected mechanical ventilation duration of at least 24 hours, using a low-oxygenation strategy did not result in a reduction of 28-day mortality compared with a high-oxygenation strategy. Clinical trial registered with the National Trial Register and the International Clinical Trials Registry Platform (NTR7376).

Alzheimer's disease (AD) and type 2 diabetes (T2D) are chronic diseases that share several pathological mechanisms, including insulin resistance and impaired insulin signalling. Their shared features have prompted the evaluation of the drugs used to manage diabetes for the treatment of AD. Insulin delivery itself has been utilized, with promising effects, in improving cognition and reducing AD related neuropathology. The most recent clinical trial involving intranasal insulin reported no slowing of cognitive decline; however, several factors may have impacted the trial outcomes. Long-acting and rapid-acting insulin analogues have also been evaluated within the context of AD with a lack of consistent outcomes. This narrative review provided insight into how targeting insulin signalling in the brain has potential as a therapeutic target for AD and provided a detailed update on the efficacy of insulin, its analogues and the outcomes of human clinical trials. We also discussed the current evidence that warrants the further investigation of the use of the mimetics of insulin for AD. These small molecules may provide a modifiable alternative to insulin, aiding in developing drugs that selectively target insulin signalling in the brain with the aim to attenuate cognitive dysfunction and AD pathologies.

Purpose: Oxygen therapy is vital in adult intensive care unit (ICU) patients, but it is indistinct whether higher or lower oxygen targets are favorable. Our aim was to update the findings of randomized controlled trials (RTCs) comparing higher and lower oxygen strategies., Materials and Methods: MEDLINE, EMBASE, and Web of Science were searched. RCTs comparing higher (liberal, hyperoxia) and lower (conservative, normoxia) oxygen in adult mechanically ventilated ICU patients were included. The main outcome was 90-day mortality; other outcomes include serious adverse events (SAE), support free days and length of stay (LOS)., Results: No significant difference was observed for 90-day mortality. A lower incidence was found for SAEs, favoring lower oxygenation (OR, 0.86; 95%CI, 0.77-0.96; I 2 13%). No differences were observed in either support free days at day 28 or ICU and hospital LOS., Conclusions: No difference was found for 90-day mortality, support free days and ICU and hospital LOS. However, a lower incidence of SAEs was found for lower oxygenation. These findings may have clinical implications for practice guidelines, yet it remains of paramount importance to continue conducting clinical trials, comparing groups with a clinically relevant contrast and focusing on the impact of important side effects., Competing Interests: Declaration of Competing Interest All authors declare to have no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In countries where the majority of young children are enrolled in professional childcare, the childcare setting constitutes an important part of children's caregiving environment. Research consistently shows that particularly the quality of the daily interactions and relationship between young children and their professional caregivers have long-term effects on a range of developmental child outcomes. Therefore, professional caregivers' capacity for establishing high quality interactions with the children in their care is an important target of intervention., Methods: A prospective, parallel, cluster-randomized wait-list controlled trial is used to test the efficacy of the attachment- and mentalization theory informed Circle of Security (COS) approach adapted to the childcare setting (COS-Classroom) on caregiver interactive skills and mind-mindedness. Participants are professional caregivers of children aged 0-2.9 years working in center-based childcare in Denmark. Approximately 31 childcare centers, corresponding to an estimated 113 caregivers, are expected to participate. The primary outcome is caregiver Sensitive responsiveness measured with the Caregiver Interactive Profile Scales (CIP-scales). Secondary outcomes include caregiver Mind-mindedness, the five remaining CIP-scales (Respect for autonomy, Structure and limit setting, Verbal communication, Developmental stimulation, and Fostering positive peer interactions), and caregivers' resources to cope with work-related stress. Data on structural factors (e.g., staff stability, caregiver-child ratio, and level of pre-service education), caregiver attachment style, acceptability and feasibility of the COS-C together with qualitative data on how the participants experience the COS-C is additionally collected to investigate moderating and confounding effects., Discussion: Examining the effectiveness of the COS-C in center-based childcare contributes to the knowledge of evidence-based intervention programs and can potentially improve the caregiver quality early childcare., Trial Registration: ClinicalTrials.gov: NCT04654533. Prospectively registered December 4, 2020, https://clinicaltrials.gov/ct2/show/NCT04654533 ., (© 2022. The Author(s).)

A high-fat diet (HFD) impairs insulin binding and signalling and may contribute to the development of insulin resistance. In addition, in vitro studies have shown that alterations in plasma membrane cholesterol influence ligand binding and downstream signalling for several receptor-tyrosine kinases (RTKs), including the insulin receptor. Using an ex vivo approach, we explored the effects of a HFD on insulin binding and signalling in mouse liver and relate these to observed changes in plasma membrane cholesterol. Mice fed a HFD demonstrated decreased insulin signalling compared to mice fed a normal chow diet (ND), indicated by a 3-fold decrease in insulin binding (P < 0.001) and a similar decrease in insulin receptor phosphorylation (~2.5-fold; P < 0.0001). Interestingly, we also observed a marked decrease in the cholesterol content of liver plasma membranes in the HFD fed mice (P < 0.0001). These effects of the HFD were found to be ameliorated by atorvastatin treatment (P < 0.0001). However, in ND mice, atorvastatin had no influence on membrane cholesterol content or insulin binding and signalling. The influence of membrane cholesterol on insulin binding and signalling was also corroborated in HepG2 cells. To the best of our knowledge, this is the first demonstration of the effects of a HFD and atorvastatin treatment on changes in plasma membrane cholesterol content and the consequent effects on insulin binding and signalling. Collectively, these findings suggest that changes in membrane cholesterol content could be an important underlying reason for the long-known effects of a HFD on the development of insulin resistance., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Oxygen therapy is a widely used intervention in acutely ill patients in the intensive care unit (ICU). It is established that not only hypoxia, but also prolonged hyperoxia is associated with poor patient-centered outcomes. Nevertheless, a fundamental knowledge gap remains regarding optimal oxygenation for critically ill patients. In this randomized clinical trial, we aim to compare ventilation that uses conservative oxygenation targets with ventilation that uses conventional oxygen targets with respect to mortality in ICU patients., Methods: The "ConservatIve versus CONventional oxygenation targets in Intensive Care patients" trial (ICONIC) is an investigator-initiated, international, multicenter, randomized clinical two-arm trial in ventilated adult ICU patients. The ICONIC trial will run in multiple ICUs in The Netherlands and Italy to enroll 1512 ventilated patients. ICU patients with an expected mechanical ventilation time of more than 24 h are randomized to a ventilation strategy that uses conservative (PaO 2 55-80 mmHg (7.3-10.7 kPa)) or conventional (PaO 2 110-150 mmHg (14.7-20 kPa)) oxygenation targets. The primary endpoint is 28-day mortality. Secondary endpoints are ventilator-free days at day 28, ICU mortality, in-hospital mortality, 90-day mortality, ICU- and hospital length of stay, ischemic events, quality of life, and patient opinion of research and consent in the emergency setting., Discussion: The ICONIC trial is expected to provide evidence on the effects of conservative versus conventional oxygenation targets in the ICU population. This study may guide targeted oxygen therapy in the future., Trial Registration: Trialregister.nl NTR7376 . Registered on 20 July, 2018., (© 2022. The Author(s).)

Objectives: In critically ill patients, dysnatremia is common, and in these patients, in-hospital mortality is higher. It remains unknown whether changes of serum sodium after ICU admission affect mortality, especially whether normalization of mild hyponatremia improves survival., Design: Retrospective cohort study., Setting: Ten Dutch ICUs between January 2011 and April 2017., Patients: Adult patients were included if at least one serum sodium measurement within 24 hours of ICU admission and at least one serum sodium measurement 24-48 hours after ICU admission were available., Interventions: None., Measurements and Main Results: A logistic regression model adjusted for age, sex, and Acute Physiology and Chronic Health Evaluation-IV-predicted mortality was used to assess the difference between mean of sodium measurements 24-48 hours after ICU admission and first serum sodium measurement at ICU admission (Δ48 hr-[Na]) and in-hospital mortality. In total, 36,660 patients were included for analysis. An increase in serum sodium was independently associated with a higher risk of in-hospital mortality in patients admitted with normonatremia (Δ48 hr-[Na] 5-10 mmol/L odds ratio: 1.61 [1.44-1.79], Δ48 hr-[Na] > 10 mmol/L odds ratio: 4.10 [3.20-5.24]) and hypernatremia (Δ48 hr-[Na] 5-10 mmol/L odds ratio: 1.47 [1.02-2.14], Δ48 hr-[Na] > 10 mmol/L odds ratio: 8.46 [3.31-21.64]). In patients admitted with mild hyponatremia and Δ48 hr-[Na] greater than 5 mmol/L, no significant difference in hospital mortality was found (odds ratio, 1.11 [0.99-1.25])., Conclusions: An increase in serum sodium in the first 48 hours of ICU admission was associated with higher in-hospital mortality in patients admitted with normonatremia and in patients admitted with hypernatremia., Competing Interests: Drs. Termorshuizen’s and de Keizer’s institutions received funding from the National Intensive Care Evaluation Foundation. Dr. Termorshuizen received funding from the Mental Health Care Institute, Rivierduinen, Leiden. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Parental stress is a known risk factor for coercive parenting and for lower coparenting quality. In the present study, we examined whether and how changes in parental stress of mothers and fathers from the pre-COVID-19 period (T1) into the height of the first lockdown in the Netherlands (T2) were linked to changes in coercive parenting of mothers and fathers and to changes in coparenting quality. A total of 96 families (46.9% lower or medium and 53.1% higher educational background), with mother, father, and child (53.1% girls; T1: M age = 3.44 years, SD = 0.32; T2: M age = 4.72 years, SD = 0.61) participated. To examine interrelations between parental stress (reported using the Parental Stress Scale), coparenting, and coercive parenting (both reported using the Parenting And Family Adjustment Scales), a multivariate Latent Change Score (LCS) model was employed. Higher initial levels of parental stress were associated with higher initial levels of coercive parenting and lower initial levels of coparenting quality. Similarly, stronger increases in parental stress were associated with stronger increases in coercive parenting and with stronger decreases in coparenting quality. Directions of associations and effect sizes were similar for mothers and fathers in all analyses. The results from the present study indicate the importance of a family systems perspective in prevention and intervention programs. Promotion of systematic family-based preventive and intervention activities by the government might support families during challenging times, as during the novel COVID-19 pandemic. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background: For active patients with a tear of the anterior cruciate ligament (ACL) who would like to return to active level of sports, the current surgical gold standard is reconstruction of the ACL. Recently, there has been renewed interest in repairing the ACL in selected patients with a proximally torn ligament. Repair of the ligament has (potential) advantages over reconstruction of the ligament such as decreased surgical morbidity, faster return of range of motion, and potentially decreased awareness of the knee. Studies comparing both treatments in a prospective randomized method are currently lacking., Methods: This study is a multicenter prospective block randomized controlled trial. A total of 74 patients with acute proximal isolated ACL tears will be assigned in a 1:1 allocation ratio to either (I) ACL repair using cortical button fixation and additional suture augmentation or (II) ACL reconstruction using an all-inside autologous hamstring graft technique. The primary objective is to assess if ACL repair is non-inferior to ACL reconstruction regarding the subjective International Knee Documentation Committee (IKDC) score at two-years postoperatively. The secondary objectives are to assess if ACL repair is non-inferior with regards to (I) other patient-reported outcomes measures (i.e. Knee Injury and Osteoarthritis Outcome Score, Lysholm score, Forgotten Joint Score, patient satisfaction and pain), (II) objective outcome measures (i.e. failure of repair or graft defined as rerupture or symptomatic instability, reoperation, contralateral injury, and stability using the objective IKDC score and Rollimeter/KT-2000), (III) return to sports assessed by Tegner activity score and the ACL-Return to Sports Index at two-year follow-up, and (IV) long-term osteoarthritis at 10-year follow-up., Discussion: Over the last decade there has been a resurgence of interest in repair of proximally torn ACLs. Several cohort studies have shown encouraging short-term and mid-term results using these techniques, but prospective randomized studies are lacking. Therefore, this randomized controlled trial has been designed to assess whether ACL repair is at least equivalent to the current gold standard of ACL reconstruction in both subjective and objective outcome scores., Trial Registration: Registered at Netherlands Trial Register ( NL9072 ) on 25th of November 2020.

There are no studies on Candida colonization and micropeptides of saliva in any patient. Therefore, we studied the effects of the salivary antimicrobial peptide histatin 5 on oral fungal colonization; subjects were subdivided into Down syndrome (D) and normal (N) groups by age: N-1 and D-1, age <20 years; N-2 and D-2, age >40 years. Histatin 5 concentration in saliva was measured by enzyme-linked immunosorbent assay. Oral Candida species were identified using CHROMagar Candida . Candida colonization was significantly enhanced in the D-1 and D-2 groups compared to the N-1 and N-2 groups. There was no predominant difference in salivary histatin 5 concentration between the D-1 and N-1 groups, but it was significantly lower in the D-2 group than in the N-2 group. Only in the N-2 group was there a correlation between the concentration of histatin 5 and total protein, while no correlation was found in the other groups. In elderly patients with Down syndrome, the decrease in histatin 5 shown in this study may lead to oral Candida colony formation. Therefore, the results of this study suggest that a deficiency of the antimicrobial peptide histatin 5 could possibly induce oral Candida infection in DS.

Celiac disease is characterized by a chronic immune-mediated inflammation of the small intestine, triggered by gluten contained in wheat, barley, and rye. Rothia aeria , a gram-positive natural colonizer of the oral cavity and the upper digestive tract is able to degrade and detoxify gluten in vitro. The objective of this study was to assess gluten-degrading activity of live and dead R. aeria bacteria in vitro, and to isolate the R. aeria gluten-degrading enzyme., Methods: After an overnight fast, Balb/c mouse were fed a 1 g pellet of standard chow containing 50% wheat (and 4% gliadin) with or without 1.6 × 10 7 live R. aeria bacteria. After 2 h, in vivo gluten degradation was assessed in gastric contents by SDS-PAGE and immunoblotting, and immunogenic epitope neutralization was assessed with the R5 gliadin ELISA assay. R. aeria enzyme isolation and identification was accomplished by separating proteins in the bacterial cell homogenate by C18 chromatography followed by gliadin zymography and mass spectrometric analysis of excised bands., Results: In mice fed with R. aeria , gliadins and immunogenic epitopes were reduced by 20% and 33%, respectively, as compared to gluten digested in control mice. Killing of R. aeria bacteria in ethanol did not abolish enzyme activity associated with the bacteria. The gluten degrading enzyme was identified as BAV86562.1, here identified as a member of the subtilisin family., Conclusion: This study shows the potential of R. aeria to be used as a first probiotic for gluten digestion in vivo, either as live or dead bacteria, or, alternatively, for using the purified R. aeria enzyme, to benefit the gluten-intolerant patient population.

Background: Little is known to what extent attitudes of ICU clinicians are influenced by new insights and recommendations to be more conservative with oxygen therapy. Our aim was to investigate whether implementation of a conservative oxygenation guideline structurally changed self-reported attitudes and actual clinical practice., Methods: After the implementation of a conservative oxygen therapy guideline in 3 teaching hospitals in the Netherlands, ICU clinicians were surveyed regarding their attitudes toward oxygen therapy. The survey results were compared with survey results taken before the introduction of the new guideline. Arterial blood gas analysis data and ventilator settings were retrieved from all patients admitted to the participating ICUs in the studied period, and changes after implementing the guideline were assessed., Results: In total, 180 ICU clinicians returned the survey. Compared to before implementation of a conservative oxygen guideline, more clinicians chose a preferred [Formula: see text] and an oxygen saturation measured from an arterial sample ([Formula: see text]) limit after implementation of the guideline. In general, clinicians reported a more conservative approach toward management of [Formula: see text] and less frequently increased the [Formula: see text]. In the period after the active implementation of the guideline, 5,840 subjects were admitted to the participating ICUs and 101,869 arterial blood gas analyses were retrieved. Actual practice changed with overall lower oxygenation levels (median [Formula: see text] 77.93 mm Hg, compared to 86.93 mm Hg before implementation) of arterial blood and a decrease of PEEP and [Formula: see text]., Conclusions: Implementing a conservative oxygenation guideline was an effective method that changed self-reported attitudes and actual clinical practice and improved adherence to conservative oxygenation targets in a short period of time., Competing Interests: Drs Grim, Helmerhorst, and de Jonge received grant support from the Netherlands Organization for Health Research and Development. The other authors have disclosed no conflicts of interest., (Copyright © 2020 by Daedalus Enterprises.)

Proline-rich proteins are associated with the formation of an acquired protein layer overlying the tooth enamel surface. Previous studies have described the antioxidant activity of salivary histatin against the hydroxyl radical from Fenton's reaction, acting as the critical reactive oxygen species. However, the role of proline-rich proteins in mitigating the oxidative stress caused by reactive oxygen species in the oral cavity remains unclear. In this study, we investigated the antioxidant effects of proline-rich proteins 2 on direct reactive oxygen species using electron spin resonance spectroscopy. For the first time, we demonstrated that proline-rich proteins 2 exhibits antioxidant activity directly against the hydroxyl radical produced by hydrogen peroxide with ultraviolet. Considering that identical results were obtained when assaying 30 residues of proline-rich proteins 2, the direct antioxidant effects against the hydroxyl radical by proline-rich proteins 2 may be related to these specific 30 residues., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2020 JCBN.)

Celiac disease (CeD) affects about 1% of most world populations. It presents a wide spectrum of clinical manifestations, ranging from minor symptoms to mild or severe malabsorption, and it may be associated with a wide variety of autoimmune diseases. CeD is triggered and maintained by the ingestion of gluten proteins from wheat and related grains. Gluten peptides that resist gastrointestinal digestion are antigenically presented to gluten specific T cells in the intestinal mucosa via HLA-DQ2 or HLA-DQ8, the necessary genetic predisposition for CeD. To date, there is no effective or approved treatment for CeD other than a strict adherence to a gluten-free diet, which is difficult to maintain in professional or social environments. Moreover, many patients with CeD have active disease despite diet adherence due to a high sensitivity to traces of gluten. Therefore, safe pharmacological treatments that complement the gluten-free diet are urgently needed. Oral enzyme therapy, employing gluten-degrading enzymes, is a promising therapeutic approach. A prerequisite is that such enzymes are active under gastro-duodenal conditions, quickly neutralize the T cell activating gluten peptides and are safe for human consumption. Several enzymes including prolyl endopeptidases, cysteine proteases and subtilisins can cleave the human digestion-resistant gluten peptides in vitro and in vivo. Examples are several prolyl endopeptidases from bacterial sources, subtilisins from Rothia bacteria that are natural oral colonizers and synthetic enzymes with optimized gluten-degrading activities. Without exception, these enzymes must cleave the otherwise unusual glutamine and proline-rich domains characteristic of antigenic gluten peptides. Moreover, they should be stable and active in both the acidic environment of the stomach and under near neutral pH in the duodenum. This review focuses on those enzymes that have been characterized and evaluated for the treatment of CeD, discussing their origin and activities, their clinical evaluation and challenges for therapeutic application. Novel developments include strategies like enteric coating and genetic modification to increase enzyme stability in the digestive tract.

Background: Over the last decade, there has been an increasing awareness for the potential harm of the administration of too much oxygen. We aimed to describe self-reported attitudes towards oxygen therapy by clinicians from a large representative sample of intensive care units (ICUs) in the Netherlands., Methods: In April 2019, 36 ICUs in the Netherlands were approached and asked to send out a questionnaire (59 questions) to their nursing and medical staff (ICU clinicians) eliciting self-reported behaviour and attitudes towards oxygen therapy in general and in specific ICU case scenarios., Results: In total, 1361 ICU clinicians (71% nurses, 24% physicians) from 28 ICUs returned the questionnaire. Of responding ICU clinicians, 64% considered oxygen-induced lung injury to be a major concern. The majority of respondents considered a partial pressure of oxygen (PaO2) of 6-10 kPa (45-75 mmHg) and an arterial saturation (SaO2) of 85-90% as acceptable for 15 minutes, and a PaO2 7-10 kPa (53-75 mmHg) and SaO2 90-95% as acceptable for 24-48 hours in an acute respiratory distress syndrome (ARDS) patient. In most case scenarios, respondents reported not to change the fraction of inspired oxygen (FiO2) if SaO2 was 90-95% or PaO2 was 12 kPa (90 mmHg)., Conclusion: A representative sample of ICU clinicians from the Netherlands were concerned about oxygen-induced lung injury, and reported that they preferred PaO2 and SaO2 targets in the lower physiological range and would adjust ventilation settings accordingly.

High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule that triggers the progression of several pro-inflammatory diseases such as diabetes, Alzheimer's disease and cancer, by inducing signals upon interaction with the receptors such as the receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs). The acidic C-terminal tail of HMGB1 is an intrinsically disordered region of the protein which is known to determine the interaction of HMGB1 to DNA and histones. This study characterizes its structural properties using a combination of circular dichroism (CD) and molecular dynamics (MD) simulations. The full-length and tail-less forms of HMGB1 were compared to rationalise the role of the acidic tail in maintaining the stability of the entire structure of HMGB1 in atomistic detail. Consistent with experimental data, the acidic tail was predicted to adopt an extended conformation that allows it to make a range of hydrogen-bonding and electrostatic interactions with the box-like domains that stabilize the overall structure of HMGB1. Absence of the acidic tail was predicted to increase structural fluctuations of all amino acids, leading to changes in secondary structure from α-helical to more hydrophilic turns along with increased exposure of multiple amino acids to the surrounding solvent. These structural changes reveal the intrinsic conformational dynamics of HMGB1 that are likely to affect the accessibility of its receptors., (© 2020 The Author(s).)

Histatin, a salivary protein, affects oral homeostasis through preservation of tooth integrity and protection against caries and fungal infections. However, the effects of histatin in the generation of oxidative stress induced by reactive oxygen species and in the oral cavity remain unclear. In this study, the effects of histatin on direct reactive oxygen species scavenging activity were examined using electron spin resonance. We demonstrated, for the first time, that histatin exhibits antioxidant activity against hydroxyl radicals generated by Fenton's reaction by metal chelation or binding. The direct antioxidant effects of histatin, along with its antimicrobial activity, may be important in the oral protection of salivary proteins., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2019 JCBN.)

There is consensus in the literature that self-esteem stems from relationships with others. In particular, it is assumed that parents play an important role in the development of children's self-esteem, also in adolescence. Despite the importance of parent-child attachment relationships for adolescents' self-esteem, we know very little about the extent to which fathers and mothers uniquely contribute to adolescents' self-esteem. The current study aims to contribute to acquiring knowledge in this research area in three ways. First, by separating the potential influences of father-child and mother-child attachment relationships on sons' and daughters' self-esteem, the current study is able to investigate the individual contribution of the father-child and mother-child attachment relationship to female and male adolescent's self-esteem. Second, by controlling for changes in the quality of the parental relationship and peer relationships the current study is able to isolate linkages between changes in adolescents' perceived quality of the parent-child attachment relationships and changes in adolescents' self-esteem. Third, by using longitudinal data and solely analyzing within-person variation, the current study is able to rule out stable confounding factors as alternative explanations. Self-reports of 542 adolescents (mean age at T1 = 13.6 years, percentage female = 0.51) from all three waves of the Dutch cohort study Social Development of Adolescents were used. The longitudinal fixed effects models showed that, for both sons and daughters, changes in the perceived quality of the mother-adolescent attachment relationship and changes in the perceived quality of the relationship between adolescents' parents were positively linked with changes in self-esteem. Changes in the perceived quality of the attachment relationship with father were only significantly linked to changes in daughters' self-esteem, not in that of sons. Contrary to the expectations, changes in peer relationships were not associated with changes in adolescents' self-esteem. These findings suggest that even though adolescents may be increasing their time spent with friends and romantic partners, perceived changes in the attachment relationships with fathers and mothers and in the wider family system are highly important for how adolescents think of and judge themselves.

There is emerging evidence of the utility of virus-like particles (VLPs) as a novel model for the study of receptor-ligand interactions in a native plasma membrane environment. VLPs consist of a viral core protein encapsulated by portions of the cell membrane with membrane proteins and receptors expressed in their native conformation. VLPs can be generated in mammalian cells by transfection with the retroviral core protein (gag). In this study, we used Chinese hamster ovary (CHO T10) cells stably overexpressing the insulin receptor (IR) to generate IR bearing VLPs. The diameter and size uniformity of VLPs were estimated by dynamic light scattering and morphological features examined by scanning electron microscopy. The presence of high affinity IR on VLPs was demonstrated by competitive binding assays (K D : 2.3 ± 0.4 nM, n = 3), which was similar to that on the parental CHO T10 cells (K D : 2.1 ± 0.4 nM, n = 3). We also report that increases or decreases in membrane cholesterol content by treatment with methyl-β-cyclodextrin (MBCD) or cholesterol pre-loaded methyl-β-cyclodextrin (cMBCD), respectively, substantially decreased insulin binding (> 30%) to both VLPs and cells, and we speculate this is due to a change in receptor disposition. We suggest that this novel finding of decreases in insulin binding in response to changes in membrane cholesterol content may largely account for the unexplained decreases in insulin signalling events previously reported elsewhere. Finally, we propose VLPs as a viable membrane model for the study of insulin-IR interactions in a native membrane environment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Detoxification of gluten immunogenic epitopes is a promising strategy for the treatment of celiac disease. Our previous studies have shown that these epitopes can be degraded in vitro by subtilisin enzymes derived from Rothia mucilaginosa, a natural microbial colonizer of the oral cavity. The challenge is that the enzyme is not optimally active under acidic conditions as encountered in the stomach. We therefore aimed to protect and maintain subtilisin-A enzyme activity by exploring two pharmaceutical modification techniques: PEGylation and Polylactic glycolic acid (PLGA) microencapsulation. PEGylation of subtilisin-A (Sub-A) was performed by attaching methoxypolyethylene glycol (mPEG, 5 kDa). The PEGylation protected subtilisin-A from autolysis at neutral pH. The PEGylated Sub-A (Sub-A-mPEG) was further encapsulated by PLGA. The microencapsulated Sub-A-mPEG-PLGA showed significantly increased protection against acid exposure in vitro. In vivo, gluten immunogenic epitopes were decreased by 60% in the stomach of mice fed with chow containing Sub-A-mPEG-PLGA (0.2 mg Sub-A/g chow) (n = 9) compared to 31.9% in mice fed with chow containing unmodified Sub-A (n = 9). These results show that the developed pharmaceutical modification can protect Sub-A from auto-digestion as well as from acid inactivation, thus rendering the enzyme more effective for applications in vivo.

Competing Interests: Competing interests: None declared.

Quality-adjusted life years are used in cost-effectiveness analyses (CEAs). To calculate QALYs, a "utility" (0-1) is used for each health state induced or prevented by the intervention. We aimed to estimate the impact of quality of life (QoL) assumptions (utilities and durations of health states) on CEAs of cervical cancer screening. To do so, 12 alternative sets of utility assumptions were retrieved from published cervical cancer screening CEAs. Two additional sets were based on empirical QoL data that were integrally obtained through two different measures (SF-6D and EQ-5D) from eight groups of women (total n = 3,087), from invitation for screening to diagnosis with cervical cancer. Per utility set we calculated the number of quality-adjusted days lost (QADL) for each relevant health state in cervical cancer screening, by multiplying the study-specific assumed disutilities (i.e., 1-utility) with study-specific durations of the loss in QoL, resulting in 14 "QADL-sets." With microsimulation model MISCAN we calculated cost-effectiveness of 342 alternative screening programs (varying in primary screening test [Human Papillomavirus (HPV) vs. cytology], starting ages, and screening interval) for each of the 14 QADL-sets. Utilities used in CEAs appeared to differ largely. We found that ten QADL-sets from the literature resulted in HPV and two in cytology as preferred primary test. The SF-6D empirical QADL-set resulted in cytology and the EQ-5D one in HPV as preferred primary test. In conclusion, assumed utilities and health state durations determine cost-effectiveness of cervical cancer screening. Also, the measure used to empirically assess utilities can be crucial for CEA conclusions., (© 2018 UICC.)

Background: Diarrheal disease from enterotoxigenic Escherichia coli (ETEC) causes significant worldwide morbidity and mortality in young children residing in endemic countries and is the leading cause of traveler's diarrhea. As ETEC enters the body through the oral cavity and cotransits the digestive tract with salivary components, we hypothesized that the antimicrobial activity of salivary proteins might extend beyond the oropharynx into the proximal digestive tract., Results: Here, we show that the salivary peptide histatin-5 binds colonization factor antigen I pili, thereby blocking adhesion of ETEC to intestinal epithelial cells. Mechanistically, we demonstrate that histatin-5 stiffens the typically dynamic pili, abolishing their ability to function as spring-like shock absorbers, thereby inhibiting colonization within the turbulent vortices of chyme in the gastrointestinal tract., Conclusions: Our data represent the first report of a salivary component exerting specific antimicrobial activity against an enteric pathogen and suggest that histatin-5 and related peptides might be exploited for prophylactic and/or therapeutic uses. Numerous viruses, bacteria, and fungi traverse the oropharynx to cause disease, so there is considerable opportunity for various salivary components to neutralize these pathogens prior to arrival at their target organ. Identification of additional salivary components with unexpectedly broad antimicrobial spectra should be a priority.

Objectives: Saliva contains biomarkers for systemic as well as oral diseases. This study was undertaken to assess the variability in the sources of such biomarkers (plasma, cells) and attempted to identify saliva deterioration markers in order to improve saliva diagnostic outcomes., Materials and Methods: Inter- and intrasubject variations in salivary gingival crevicular fluid levels were determined by measuring salivary albumin and transferrin levels. The purity of collected glandular secretions was determined by bacterial culture, and the variability in epithelial cell numbers by cell counting and optical density measurement. Saliva sample deterioration markers were identified by RP-HPLC and LC-ESI-MS/MS., Results: Tenfold variations were observed in plasma-derived albumin and transferrin levels, emphasizing the need for biomarker normalization with respect to plasma contributions to saliva. Epithelial cell levels varied 50-fold in samples collected before and after a meal. Salivary fungal levels varied within subjects and among subjects from 0 to >1,000 colony-forming units per milliliter. In saliva samples incubated for various time intervals at 37°C, five peptides were identified that steadily increased in intensity over time and which could be explored as "deterioration markers.", Conclusion: Taking saliva characteristics appropriately into account will help realize the promise that this body fluid is suitable to be exploited for reliable healthcare monitoring and surveillance., (Published 2017. This article is a U.S. Government work and is in the public domain in the USA.)

Aim: To investigate whether coeliac disease (CD) was associated with periodontitis among a nationally representative sample of US adults., Materials and Methods: The National Health and Nutrition Examination Survey (NHANES) 2009-2012 enrolled 6,661 subjects with full-mouth periodontal examination and serological testing for antitissue transglutaminase (tTg) and antiendomysial (EMA) antibodies. CD was defined as (i) self-reported physician diagnosis while on a gluten-free diet; or (ii) tTg levels >10.0 U/ml and positive EMA results. Positive serology without self-reported diagnosis was defined as undiagnosed CD (UdxCD). Periodontitis was defined according to the CDC/AAP definition. Multivariable linear and logistic models were used to regress the mean probing depth (PD) or attachment loss (AL) outcomes across CD categories (none, diagnosed and undiagnosed)., Results: The prevalence of moderate/severe periodontitis and diagnosed/undiagnosed CD was 40% and 0.74%, respectively. Mean AL was lower among those with CD although results were not statistically significant (p = .67). The odds of periodontitis among individuals with diagnosed and undiagnosed CD were: 0.5(0.22, 1.16) and 0.62(0.1, 3.75), respectively. Mean PD levels among those without CD or with diagnosed or undiagnosed CD were 1.49 ± 0.02, 1.36 ± 0.11 and 1.31 ± 0.11 (p = .03)., Conclusion: CD is associated with modestly lower levels of mean PD but was not associated with mean AL or periodontitis. Larger studies are necessary to enhance precision and strengthen conclusions., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Although oxygen is generally administered in a liberal manner in the perioperative setting, the effects of oxygen administration on dynamic cardiovascular parameters, filling status and cerebral perfusion have not been fully unraveled. Our aim was to study the acute hemodynamic and microcirculatory changes before, during and after arterial hyperoxia in mechanically ventilated patients after coronary artery bypass grafting (CABG) surgery., Methods: This was a single-center physiological study in a tertiary care ICU in the Netherlands. Twenty-two patients scheduled for ICU admission after elective CABG were enrolled in the study between September 2014 and September 2015. In the ICU, patients were exposed to a fraction of inspired oxygen (FiO 2 ) of 90% allowing a 15-min wash-in period. Various hemodynamic parameters were measured using direct pressure signals and continuous arterial waveform analysis at three sequential time points: before, during and after hyperoxia., Results: During a 15-min exposure to a fraction of inspired oxygen (FiO 2 ) of 90%, the partial pressure of arterial oxygen (PaO 2 ) and arterial oxygen saturation (SaO 2 ) were significantly higher. The systemic resistance increased (P < 0.0001), without altering the heart rate. Stroke volume variation and pulse pressure variation decreased slightly. The cardiac output did not significantly decrease (P = 0.08). Mean systemic filling pressure and arterial critical closing pressure increased (P < 0.01whereas the percentage of perfused microcirculatory vessels decreased (P < 0.01). Other microcirculatory parameters and cerebral blood flow velocity showed only slight changes., Conclusions: We found that short-term hyperoxia affects hemodynamics in ICU patients after CABG. This was translated in several changes in central circulatory variables, but had only slight effects on cardiac output, cerebral blood flow and the microcirculation. Clinical trial registration Netherlands Trial Register: NTR5064.

Background: Mechanical ventilation and hyperoxia have the potential to independently promote lung injury and inflammation. Our purpose was to study both time- and dose-dependent effects of supplemental oxygen in an experimental model of mechanically ventilated mice., Methods: Healthy male C57Bl/6J mice, aged 9-10 weeks, were intraperitoneally anesthetized and randomly assigned to the mechanically ventilated group or the control group. In total, 100 mice were tracheotomized and mechanically ventilated for either 8 or 12 h after allocation to different settings for the applied fractions of inspired oxygen (FiO 2 , 30, 50, or 90%) and tidal volumes (7.5 or 15 ml/kg). After euthanisation arterial blood, bronchoalveolar lavage fluid (BALf) and tissues were collected for analyses., Results: Mechanical ventilation significantly increased the lung injury score (P < 0.05), mean protein content (P < 0.001), and the mean number of cells (P < 0.01), including neutrophils in BALf (P < 0.001). In mice ventilated for 12 h, a significant increase in TNF-α, IFN-γ, IL-1β, IL-10, and MCP-1 (P < 0.01) was observed with 90% FiO 2 , whereas IL-6 showed a decreasing trend (P for trend = 0.03) across FiO 2 groups. KC, MIP-2, and sRAGE were similar between FiO 2 groups. HMGB-1 was significantly higher in BALf of mechanically ventilated mice compared to controls and showed a gradual increase in expression with increasing FiO 2 . Cytokine and chemokine levels in BALf did not markedly differ between FiO 2 groups after 8 h of ventilation. Differences between the tidal volume groups were small and did not appear to significantly interact with the oxygen levels., Conclusions: We demonstrated a severe vascular leakage and a pro-inflammatory pulmonary response in mechanically ventilated mice, which was enhanced by severe hyperoxia and longer duration of mechanical ventilation. Prolonged ventilation with high oxygen concentrations induced a time-dependent immune response characterized by elevated levels of neutrophils, cytokines, and chemokines in the pulmonary compartment.

Background: Opioid pain medication is frequently given to patients recovering from a surgical procedure for an extremity fracture in spite of evidence that acetaminophen may be adequate. The aim of this study was to determine whether prescription of step 1 pain medication (acetaminophen) is noninferior to step 2 pain medication (acetaminophen and tramadol) after operative treatment of an extremity fracture., Methods: Fifty-two patients with a single extremity fracture were randomized from July 2012 to March 2015 in this 2-week follow-up, noninferiority trial in a level-I trauma center in the Netherlands. Patients were randomly assigned to receive step 1 (acetaminophen) or step 2 (acetaminophen and tramadol) medication in standard doses on an as-needed basis on discharge. Intention-to-treat and per-protocol analyses were conducted. The primary outcome was self-reported satisfaction with pain relief measured on an 11-point ordinal scale. The hypothesis being tested was formulated before the collection of data. The mean differences between the groups were reported for intention-to-treat and per-protocol analyses., Results: A total of 52 patients, with equal baseline characteristics, were analyzed in this study; the step 1 group consisted of 27 subjects and the step 2 group consisted of 25 subjects. The mean satisfaction with pain management was 8.3 for step 1 and 8.5 for step 2 medications. This mean difference of 0.2 point (95% confidence interval [CI], -0.78 to 1.30 points) did not exceed the noninferiority margin of 2.0 points, indicating that step 1 was noninferior to step 2. A similar result was found in the per-protocol analysis (mean difference, 0.2 point [95% CI, -1.03 to 1.57 points])., Conclusions: This study offers evidence to suggest that prescription of acetaminophen is not inferior compared with acetaminophen and tramadol in patients who underwent operative treatment for an extremity fracture. Given that tramadol has more side effects and is potentially habit-forming, acetaminophen should be considered the mainstay for pain relief in patients recovering from extremity fracture surgical procedures., Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Background: Despite the introduction of Human papillomavirus (HPV) vaccination in national immunization programs (NIPs), vaccination rates in most countries remain relatively low. An understanding of the reasons underlying decisions about whether to vaccinate is essential in order to promote wider spread of HPV vaccination. This is particularly important in relation to policies seeking to address shortfalls in current HPV campaigns. The aim of this study was to explore prevailing perspectives concerning HPV vaccination among girls, boys, and parents, and so to identify potential determinants of HPV vaccination decisions in these groups., Method: Perspectives were explored using Q-methodology. Forty-seven girls, 39 boys, and 107 parents in the Netherlands were asked to rank a comprehensive set of 35 statements, assembled based on the health belief model (HBM), according to their agreement with them. By-person factor analysis was used to identify common patterns in these rankings, which were interpreted as perspectives on HPV vaccination. These perspectives were further interpreted and described using data collected with interviews and open-ended questions., Results: The analysis revealed four perspectives: "prevention is better than cure," "fear of unknown side effects," "lack of information and awareness," and "my body, my choice." The first two perspectives and corresponding determinants of HPV vaccination decisions were coherent and distinct; the third and fourth perspectives were more ambiguous and, to some extent, incoherent, involving doubt and lack of awareness and information (perspective 3), and overconfidence (perspective 4)., Conclusions: Given the aim of publically funded vaccination programs to minimize the spread of HPV infection and HPV-related disease and the concerns about current uptake levels, our results indicate that focus should be placed on increasing awareness and knowledge, in particular among those in a modifiable phase.

The United States and Canada are in the midst of an epidemic of the use, misuse and overdose of opioids, and deaths related to overdose. This is the direct result of overstatement of the benefits and understatement of the risks of using opioids by advocates and pharmaceutical companies. Massive amounts of prescription opioids entered the community and were often diverted and misused. Most other parts of the world achieve comparable pain relief using fewer opioids. The misconceptions about opioids that created this epidemic are finding their way around the world. There is particular evidence of the increased prescription of strong opioids in Europe. Opioids are addictive and dangerous. Evidence is mounting that the best pain relief is obtained through resilience. Opioids are often prescribed when treatments to increase resilience would be more effective. Cite this article: Bone Joint J 2017;99-B:856-64., (©2017 The British Editorial Society of Bone & Joint Surgery.)

Background: Use of ethinylestradiol, one of the active ingredients in combined oral contraceptives, affects the incidence of venous thrombosis. To explain why some women develop thrombosis when using oral contraceptives and others do not, we hypothesized a role for the first-pass metabolism of ethinylestradiol in the liver. We set out to determine the association between genetic variation in the first-pass metabolism of ethinylestradiol, venous thrombosis risk and the effect on Sex-hormone-binding-globulin (SHBG) levels., Methods: Premenopausal women were included from two case-control studies: LETS (103 cases; 159 controls) and MEGA (397 cases; 796 controls). Haplotype-tagging SNPs were selected in 11 candidate genes; COMT, CYP1A2, CYP2C9, CYP3A4, CYP3A5, SULT1A1, SULT1E1, UGT1A1, UGT1A3, UGT1A9, UGT2B7. Venous thrombosis risk was expressed as odds ratios (OR) with 95% confidence intervals (CI). For SHBG levels, mean differences with 95%CI were estimated in combined oral contraceptive-using control subjects from the MEGA study., Results: Two copies of haplotype D in the UGT2B7 gene increased venous thrombosis risk (OR LETS : 3.78; OR MEGA : 2.61) as well as SHBG levels (mean difference 27.6nmol/L, 95%CI: -61.7 to 116.9 compared with no copies) in oral contraceptive users and not in non-users. In oral contraceptive users, haplotype A and B in the CYP3A4 gene were associated with venous thrombosis risk, but not in non-users; however, the effect on SHBG levels was not directional with the risk. None of the other haplotypes were associated with venous thrombosis., Conclusion: Genetic variation in the UGT2B7 gene may, in part, explain venous thrombosis risk in combined oral contraceptive users., (Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

The acquired enamel pellicle is an oral, fluid-derived protein layer that forms on the tooth surface. It is a biologically and clinically important integument that protects teeth against enamel demineralization, and abrasion. Tooth surfaces are exposed to different proteinaceous microenvironments depending on the enamel location. For instance, tooth surfaces close to the gingival sulcus contact serum proteins that emanate via this sulcus, which may impact pellicle composition locally. The aims of this study were to define the major salivary and serum components that adsorb to hydroxyapatite, to study competition among them, and to obtain preliminary evidence in an in vivo saliva/serum pellicle model. Hydroxyapatite powder was incubated with saliva and serum, and the proteins that adsorbed were identified by mass spectrometry. To study competition, saliva and serum proteins were labeled with CyDyes, mixed in various proportions, and incubated with hydroxyapatite. In vivo competition was assessed using a split-mouth design, with half the buccal tooth surfaces coated with serum and the other half with saliva. After exposure to the oral environment for 0 min, 30 min and 2 h, the pellicles were analyzed by SDS-PAGE. In pure saliva- or serum-derived pellicles, 82 and 84 proteins were identified, respectively. When present concomitantly, salivary protein adsorbers effectively competed with serum protein adsorbers for the hydroxyapatite surface. Specifically, acidic proline-rich protein, cystatin, statherin and protein S100-A9 proteins competed off apolipoproteins, complement C4-A, haptoglobin, transthyretin and serotransferrin. In vivo evidence further supported the replacement of serum proteins by salivary proteins. In conclusion, although significant numbers of serum proteins emanate from the gingival sulcus, their ability to participate in dental pellicle formation is likely reduced in the presence of strong salivary protein adsorbers. The functional properties of the acquired enamel pellicle will therefore be mostly dictated by the salivary component.

Celiac disease (CD) is a chronic immune-mediated enteropathy induced by dietary gluten in genetically predisposed individuals. Saliva harbors the second highest bacterial load of the gastrointestinal (GI) tract after the colon. We hypothesized that enzymes produced by oral bacteria may be involved in gluten processing in the intestine and susceptibility to celiac disease. The aim of this study was to investigate salivary enzymatic activities and oral microbial profiles in healthy subjects versus patients with classical and refractory CD. Stimulated whole saliva was collected from patients with CD in remission ( n = 21) and refractory CD (RCD; n = 8) and was compared to healthy controls (HC; n = 20) and subjects with functional GI complaints ( n = 12). Salivary gluten-degrading activities were monitored with the tripeptide substrate Z-Tyr-Pro-Gln-pNA and the α-gliadin-derived immunogenic 33-mer peptide. The oral microbiome was profiled by 16S rRNA-based MiSeq analysis. Salivary glutenase activities were higher in CD patients compared to controls, both before and after normalization for protein concentration or bacterial load. The oral microbiomes of CD and RCD patients showed significant differences from that of healthy subjects, e.g., higher salivary levels of lactobacilli ( P < 0.05), which may partly explain the observed higher gluten-degrading activities. While the pathophysiological link between the oral and gut microbiomes in CD needs further exploration, the presented data suggest that oral microbe-derived enzyme activities are elevated in subjects with CD, which may impact gluten processing and the presentation of immunogenic gluten epitopes to the immune system in the small intestine. IMPORTANCE Ingested gluten proteins are the triggers of intestinal inflammation in celiac disease (CD). Certain immunogenic gluten domains are resistant to intestinal proteases but can be hydrolyzed by oral microbial enzymes. Very little is known about the endogenous proteolytic processing of gluten proteins in the oral cavity. Given that this occurs prior to gluten reaching the small intestine, such enzymes are likely to contribute to the composition of the gluten digest that ultimately reaches the small intestine and causes CD. We demonstrated that endogenous salivary protease activities are incomplete, likely liberating peptides from larger gluten proteins. The potentially responsible microbes were identified. The study included refractory CD patients, who have been studied less with regard to CD pathogenesis., (Copyright © 2017 American Society for Microbiology.)

We evaluated late effects of AdhAQP1 administration in five subjects in a clinical trial for radiation-induced salivary hypofunction (http://www.clinicaltrials.gov/ct/show/NCT00372320?order=). All were identified as initially responding to human aquaporin-1 (hAQP1) gene transfer. They were followed for 3-4 years after AdhAQP1 delivery to one parotid gland. At intervals we examined salivary flow, xerostomic symptoms, saliva composition, vector presence and efficacy in the targeted gland, clinical laboratory data and adverse events. All displayed marked increases (71-500% above baseline) in parotid flow 3-4.7 years after treatment, with improved symptoms for ~2-3 years. There were some changes in [Na + ] and [Cl - ] consistent with elevated salivary flow, but no uniform changes in secretion of key parotid proteins. There were no clinically significant adverse events, nor consistent negative changes in laboratory parameters. One subject underwent a core needle biopsy of the targeted parotid gland 3.1 years post treatment and displayed evidence of hAQP1 protein in acinar, but not duct, cell membranes. All subjects responding to hAQP1 gene transfer initially had benefits for much longer times. First-generation adenoviral vectors typically yield transit effects, but these data show beneficial effects can continue years after parotid gland delivery.

Objective: Women exposed to diethylstilbestrol in utero (DES) have an increased risk of clear cell adenocarcinoma (CCA) of the vagina and cervix, while their risk of non-CCA invasive cervical cancer is still unclear., Methods: We studied the risk of pre-cancerous (CIN) lesions and non-CCA invasive cervical cancer in a prospective cohort of 12,182 women with self-reported DES exposure followed from 2000 till 2008. We took screening behavior carefully into account. Incidence was obtained through linkage with the Netherlands Nationwide Pathology database (PALGA). General population data were also derived from PALGA., Results: The incidence of CIN1 was increased (Standardized Incidence Ratio (SIR)=2.8, 95% Confidence Interval (CI)=2.3 to 3.4), but no increased risk was observed for CIN2+ (CIN2, CIN3 or invasive cancer) compared to the screened general population (SIR=1.1, 95% CI=0.95 to1.4). Women with DES-related malformations had increased risks of both CIN1 and CIN2+ (SIR=4.1, 95%CI=3.0 to 5.3 and SIR=1.5, 95%CI=1.1 to 2.0, respectively). For CIN2+, this risk increase was largely restricted to women with malformations who were more intensively screened., Conclusions: An increased risk of CIN1 among DES daughters was observed, especially in women with DES-related malformations, probably mainly due to screening. The risk of CIN2+ (including cancer) was not increased. However, among DES daughters with DES-related malformations a true small risk increase for non-CCA cervical cancer cannot be excluded., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Emerging evidence has shown the potential risks of arterial hyperoxia, but the lack of a clinical definition and methodologic limitations hamper the interpretation and clinical relevance of previous studies. Our purpose was to evaluate previously used and newly constructed metrics of arterial hyperoxia and systematically assess their association with clinical outcomes in different subgroups in the ICU., Design: Observational cohort study., Setting: Three large tertiary care ICUs in the Netherlands., Patients: A total of 14,441 eligible ICU patients., Interventions: None., Measurements and Main Results: In total, 295,079 arterial blood gas analyses, including the PaO2, between July 2011 and July 2014 were extracted from the patient data management system database. Data from all admissions with more than one PaO2 measurement were supplemented with anonymous demographic and admission and discharge data from the Dutch National Intensive Care Evaluation registry. Mild hyperoxia was defined as PaO2 between 120 and 200 mm Hg; severe hyperoxia as PaO2 greater than 200 mm Hg. Characteristics of existing and newly constructed metrics for arterial hyperoxia were examined, and the associations with hospital mortality (primary outcome), ICU mortality, and ventilator-free days and alive at day 28 were retrospectively analyzed using regression models in different subgroups of patients. Severe hyperoxia was associated with higher mortality rates and fewer ventilator-free days in comparison to both mild hyperoxia and normoxia for all metrics except for the worst PaO2. Adjusted effect estimates for conditional mortality were larger for severe hyperoxia than for mild hyperoxia. This association was found both within and beyond the first 24 hours of admission and was consistent for large subgroups. The largest point estimates were found for the exposure identified by the average PaO2, closely followed by the median PaO2, and these estimates differed substantially between subsets. Time spent in hyperoxia showed a linear and positive relationship with hospital mortality., Conclusions: Our results suggest that we should limit the PaO2 levels of critically ill patients within a safe range, as we do with other physiologic variables. Analytical metrics of arterial hyperoxia should be judiciously considered when interpreting and comparing study results and future studies are needed to validate our findings in a randomized fashion design.