Membrane-based microfluidic systems for medical and biological applications.

Microfluidic devices with integrated membranes that enable control of mass transport in constrained environments have shown considerable growth over the last decade. Membranes are a key component in several industrial processes such as chemical, pharmaceutical, biotechnological, food, and metallurgy separation processes as well as waste management applications, allowing for modular and compact systems. Moreover, the miniaturization of a process through microfluidic devices leads to process intensification together with reagents, waste and cost reduction, and energy and space savings. The combination of membrane technology and microfluidic devices allows therefore magnification of their respective advantages, providing more valuable solutions not only for industrial processes but also for reproducing biological processes. This review focuses on membrane-based microfluidic devices for biomedical science with an emphasis on microfluidic artificial organs and organs-on-chip. We provide the basic concepts of membrane technology and the laws governing mass transport. The role of the membrane in biomedical microfluidic devices, along with the required properties, available materials, and current challenges are summarized. We believe that the present review may be a starting point and a resource for researchers who aim to replicate a biological phenomenon on-chip by applying membrane technology, for moving forward the biomedical applications.

ß-glycerophosphate, not low magnitude fluid shear stress, increases osteocytogenesis in the osteoblast-to-osteocyte cell line IDG-SW3.

AIM: As osteoblasts deposit a mineralized collagen network, a subpopulation of these cells differentiates into osteocytes. Biochemical and mechanical stimuli, particularly fluid shear stress (FSS), are thought to regulate this, but their relative influence remains unclear. Here, we assess both biochemical and mechanical stimuli on long-term bone formation and osteocytogenesis using the osteoblast-osteocyte cell line IDG-SW3. METHODS: Due to the relative novelty and uncommon culture conditions of IDG-SW3 versus other osteoblast-lineage cell lines, effects of temperature and media formulation on matrix deposition and osteocytogenesis were initially characterized. Subsequently, the relative influence of biochemical (ß-glycerophosphate (ßGP) and ascorbic acid 2-phosphate (AA2P)) and mechanical stimulation on osteocytogenesis was compared, with intermittent application of low magnitude FSS generated by see-saw rocker. RESULTS: ßGP and AA2P supplementation were required for mineralization and osteocytogenesis, with 33°C cultures retaining a more osteoblastic phenotype and 37°C cultures undergoing significantly higher osteocytogenesis. ßGP concentration positively correlated with calcium deposition, whilst AA2P stimulated alkaline phosphatase (ALP) activity and collagen deposition. We demonstrate that increasing ßGP concentration also significantly enhances osteocytogenesis as quantified by the expression of green fluorescent protein linked to Dmp1. Intermittent FSS (~0.06 Pa) rocker had no effect on osteocytogenesis and matrix deposition. CONCLUSIONS: This work demonstrates the suitability and ease with which IDG-SW3 can be utilized in osteocytogenesis studies. IDG-SW3 mineralization was only mediated through biochemical stimuli with no detectable effect of low magnitude FSS. Osteocytogenesis of IDG-SW3 primarily occurred in mineralized areas, further demonstrating the role mineralization of the bone extracellular matrix has in osteocyte differentiation.

Effects of Early and Late Time-Restricted Feeding on Parameters of Metabolic Health: An Explorative Literature Assessment.

Chrono-nutrition (meal timing) aligns food consumption with one's circadian rhythm. The first meal (e.g., breakfast) likely promotes synchronization of peripheral circadian clocks, thereby supporting metabolic health. Time-restricted feeding (TRF) has been shown to reduce body weight (BW) and/or improve cardiovascular biomarkers. In this explorative literature assessment, 13 TRF randomized controlled trials (RCTs) were selected from PubMed and Scopus to evaluate the effects of early (eTRF: first meal before 10:30 a.m.) and late TRF (lTRF: first meal after 11:30 a.m.) on parameters of metabolic health. Although distinct variations in study design were evident between reports, TRF consistently decreased energy intake (EI) and BW, and improved insulin resistance as well as systolic blood pressure. eTRF seemed to have a greater beneficial effect than lTRF on insulin resistance (HOMA-IR). Importantly, most studies did not appear to consider chronotype in their evaluation, which may have underestimated TRF effects. TRF intervention may be a promising approach for risk reduction of human metabolic diseases. To conclusively determine benefits of TRF and identify clear differences between eTRF and lTRF, future studies should be longer-term (≥8 weeks) with well-defined (differences in) feeding windows, include participants chronotypically matching the intervention, and compare outcomes to those of control groups without any dietary limitations.

A cross-sectional study on the dietary patterns of multiethnic Malaysian preschoolers and their sociodemographic determinants.

Early childhood is a critical developmental stage where established dietary patterns can impact lifelong health outcomes. This study investigates dietary patterns and their relationships with sociodemographic factors among Malaysian preschoolers. A total of 643 preschoolers of Malay, Indian, Chinese and other ethnicities participating in South East Asian Nutrition Surveys (SEANUTS II) were included. Dietary intake was assessed using a single triple-pass 24-h dietary recall method. Dietary patterns were derived using principal component analysis and their association with sociodemographic factors was determined using complex sampling logistic regressions. Five dietary patterns were identified: "healthy eating," "wholegrains and starchy vegetables," "high salt and sugar," "Western food," and "sugary drinks and legumes". Having older siblings was inversely associated with a "healthy eating" pattern (adjusted OR: 0.54, 95% CI: 0.33-0.87). Malay ethnicity was associated with higher odds of adhering to the "high salt and sugar" pattern (adjusted OR: 4.12, 95% CI: 2.20-7.75). Meanwhile, children living in urban areas (adjusted OR: 1.76, 95% CI: 1.03-3.01), those from middle-income families (adjusted OR: 3.20, 95% CI: 1.38-7.40) and whose fathers were overweight (adjusted OR: 2.79, 95% CI: 1.58-4.94) showed a higher association with "Western food" pattern. Conversely, children whose mothers had overweight were less likely to adhere to the "Western food" pattern (adjusted OR: 0.50, 95% CI: 0.30-0.83). Older age was significantly associated with a greater likelihood of the "sugary drinks and legumes" pattern (adjusted OR: 3.99, 95% CI: 1.75-9.06). There was no significant association between "wholegrains and starchy vegetables" pattern with sociodemographic characteristics (all p > 0.05). These findings suggest that ethnicity, age, residence area, having older siblings, parental weight status and household income level are associated with dietary patterns among multiethnic preschoolers in Malaysia. Thus, these sociodemographic characteristics should be considered when designing targeted dietary strategies and interventions for preschoolers.

Assessing friction and damage of cell monolayers on soft substrates in vitro.

In the area of surgical applications, understanding the interaction between medical device materials and tissue is important since this interaction may cause complications. The interaction often consists of a cell monolayer touching the medical device that can be mimicked in vitro. Prominent examples of this are contact lenses, where epithelial cells interact with the contact lens, or stents and catheters, which are in contact with endothelial cells. To investigate those interactions, in previous studies, expensive microtribometers were used to avoid pressures in the contact area far beyond physiologically relevant levels. Here, we aim to present a new methodology that is cost- and time-efficient, more accessible than those used previously and allows for the application of more realistic pressures, while permitting a quantification of the damage caused to the monolayer. For this, a soft polydimethylsiloxane is employed that better mimics the mechanical properties of blood vessels than materials used in other studies. Furthermore, a technique to account for misalignments within the experiment set-up is presented. This is carried out using the raw spatial and force data recorded by the tribometer and adjusting for misalignments. The methodology is demonstrated using an endothelial cell (human umbilical vein endothelial cells) monolayer.

Short-term outcomes of early intensive neurorehabilitation for prolonged disorders of consciousness: A prospective cohort study.

BACKGROUND: Advances in medical care have increased survival in people with severe brain injuries and with that the number of survivors with prolonged disorders of consciousness (PDOC) has increased. In the literature, early intensive neurorehabilitation (EIN) for people with PDOC is recommended to achieve the best possible outcomes. OBJECTIVES: To evaluate the frequency and extent of recovery of consciousness, mortality, complications, pain and discomfort, and medication during a nationwide EIN programme in people with PDOC after acquired brain injury. We hypothesized that level of consciousness would improve in half of people with PDOC. METHODS: Prospective cohort study. People with PDOC aged 16 years and older admitted to the EIN department centralized in a single rehabilitation centre in the Netherlands (Libra Rehabilitation & Audiology) were included. The EIN delivers a subacute medical level of care and rehabilitation for a maximum duration of 14 weeks. The outcome measures were level of consciousness (CRS-R), mortality, number of complications, medication and pain/discomfort (NCS-R). RESULTS: Of the 104 people included, 68 % emerged to a minimal conscious state with command-following or higher during EIN and 44 % regained consciousness. Mortality during EIN was 6 %, and 50 % of deaths followed a non-treatment decision or withdrawal of life-sustaining treatment. Almost all participants had at least 1 medical complication, leading to hospital readmission for 30 %. 73 % showed no pain or discomfort. During EIN, cardiovascular medication and analgesics were reduced by 15 %. CONCLUSIONS: During the EIN programme, a large percentage of people with PDOC regained at least a minimal conscious state or even consciousness. These outcomes and the frequent medical complications in these people suggest that intensive specialized care should be offered to all people with PDOC. The outcomes of this study might help health professionals to better inform the families of people with PDOC about the short-term prognosis of PDOC. PROTOCOL REGISTRATION NUMBER: The Dutch Trial Register, NL 8138.

Robot-assisted Partial Nephrectomy for Hilar and Nonhilar Renal Masses: Comparison of Perioperative, Oncological, and Functional Results in a Multicentre Prospective Cohort (NEPRAH Study, UroCCR 175).

BACKGROUND AND OBJECTIVE: A hilar location for a renal tumour is sometimes viewed as a limiting factor for safe partial nephrectomy. Our aim was to evaluate perioperative, oncological, and functional outcomes of robot-assisted partial nephrectomy (RAPN) for hilar tumours (RAPN-H) in comparison to RAPN for nonhilar tumours (RAPN-NH). METHODS: We conducted an observational, multicentre cohort study using prospectively collected data from the French Research Network on Kidney Cancer (UroCCR). The registry includes data for 3551 patients who underwent RAPN for localised or locally advanced renal masses between 2010 and 2023 in 29 hospitals in France. We studied the impact of a hilar location on surgery, postoperative renal function, tumour characteristics, and survival. We also compared rates of trifecta achievement (warm ischaemia time [WIT] <25 min, negative surgical margins, and no perioperative complications) between the groups. Finally, we performed a subgroup analysis of RAPN without vascular clamping. Variables were compared in univariable analysis and using multivariable linear, logistic, and Cox proportional-hazards models adjusted for relevant patient and tumour covariates. KEY FINDINGS AND LIMITATIONS: The analytical population included 3451 patients, of whom 2773 underwent RAPN-NH and 678 underwent RAPN-H. Longer WIT (ß = 2.4 min; p < 0.01), longer operative time (ß = 11.4 min; p < 0.01) and a higher risk of postoperative complications (odds ratio 1.33; p = 0.05) were observed in the hilar group. Blood loss, the perioperative transfusion rate, postoperative changes in the estimated glomerular filtration rate, and trifecta achievement rates were comparable between the groups (p > 0.05). At mean follow-up of 31.9 mo, there was no significant difference in recurrence-free survival (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.58-1.2; p = 0.3), cancer-specific survival (HR 1.1, 95% CI 0.48-2.6; p = 0.79), or overall survival (HR 0.89, 95% CI 0.52-1.53; p = 0.69). CONCLUSIONS AND CLINICAL IMPLICATIONS: Patient and tumour characteristics rather than just hilar location should be the main determinants of the optimal surgical strategy for hilar tumours. PATIENT SUMMARY: We found that kidney tumours located close to major kidney blood vessels led to a longer operation and a higher risk of complications during robot-assisted surgery to remove the tumour. However, tumours in these locations were not related to a higher risk of kidney function loss, cancer recurrence, or death.

A Biomarker-Based Diagnostic Model for Cardiac Dysfunction in Childhood Cancer Survivors.

Background: Childhood cancer survivors at risk for heart failure undergo lifelong echocardiographic surveillance. Previous studies reported the limited diagnostic accuracy of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) in detecting left ventricular (LV) dysfunction. However, potential enhanced diagnostic accuracy through the combination of biomarkers and clinical characteristics has been suggested. Objectives: The aim of this study was to develop and internally validate a diagnostic model that combines cardiac biomarkers with clinical characteristics for effectively ruling in or ruling out LV dysfunction in childhood cancer survivors. Methods: A multicenter cross-sectional study included 1,334 survivors (median age 34.2 years) and 278 siblings (median age 36.8 years). Logistic regression models were developed and validated through bootstrapping, combining biomarkers with clinical characteristics. Results: Abnormal NT-proBNP levels were observed in 22.1% of survivors compared with 5.4% of siblings, whereas hs-cTnT levels exceeding 10 ng/L were uncommon in both survivors (5.9%) and siblings (5.0%). The diagnostic models demonstrated improvement upon the addition of NT-proBNP and hs-cTnT to clinical characteristics, resulting in an increased C statistic from 0.69 to 0.73 for LV ejection fraction (LVEF) <50% and a more accurate prediction of more severe LV dysfunction, with the C statistic increasing from 0.80 to 0.86 for LVEF <45%. For LVEF <50% (prevalence 10.9%), 16.9% of survivors could be effectively ruled out with high sensitivity (95.4%; 95% CI: 90.4%-99.3%) and negative predictive value (97.5%; 95% CI: 94.6%-99.7%). Similarly, for LVEF <45% (prevalence 3.4%), 53.0% of survivors could be ruled out with moderate to high sensitivity (91.1%; 95% CI: 79.2%-100%) and high negative predictive value (99.4%; 95% CI: 98.7%-100%). Conclusions: The biomarker-based diagnostic model proves effective in ruling out LV dysfunction, offering the potential to minimize unnecessary surveillance echocardiography in childhood cancer survivors. External validation is essential to confirm these findings. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors; A DCOG LATER Study; https://onderzoekmetmensen.nl/nl/trial/23641).

Different subtypes of chronic fatigue in childhood cancer survivors: A DCCSS LATER study.

INTRODUCTION: The aim of the current study was to investigate whether subtypes of chronic fatigue (CF) can be identified in childhood cancer survivors (CCS), and if so, to determine the characteristics of participants with a specific subtype. METHODS: Participants were included from the nationwide DCCSS LATER cohort. The Checklist Individual Strength (CIS) was completed to assess fatigue. Participants with CF (scored ≥35 on the fatigue severity subscale and indicated to suffer from fatigue for ≥6 months) were divided into subgroups using two-step cluster analysis based on the CIS concentration, motivation, and physical activity subscales. Differences between groups on demographics, psychosocial, lifestyle, and treatment-related variables were determined using ANOVA and chi-square analyses (univariable) and multinomial regression analysis (multivariable). RESULTS: A total of 1910 participants participated in the current study (n = 450 with CF; n = 1460 without CF). Three CF subgroups were identified: Subgroup 1 (n = 133, 29% of participants) had CF with problems in physical activity; Subgroup 2 (n = 111, 25% of participants) had CF with difficulty concentrating; and Subgroup 3 (n = 206, 46% of participants) had multi-dimensional CF. Compared to Subgroup 1, Subgroup 2 more often reported sleep problems, limitations in social functioning, and less often have more than two comorbidities. Subgroup 3 more often reported depression, sleep problems, a lower self-esteem, and limitations in social functioning and a lower educational level compared to Subgroup 1. CONCLUSION: Different subgroups of CCS with CF can be identified based on fatigue dimensions physical activity, motivation and concentration. Results suggest that different intervention strategies, tailored for each subgroup, might be beneficial.

Unhealthy lifestyle behaviors, overweight, and obesity among childhood cancer survivors in the Netherlands: A DCCSS LATER study.

BACKGROUND: The objective of this study was to examine the prevalence of unhealthy lifestyle behaviors, overweight, and obesity in Dutch childhood cancer survivors (CCSs) compared with sibling controls and the Dutch general population. Other aims were to assess associated factors of unhealthy lifestyle behaviors, overweight, and obesity and to identify subgroups of CCSs at risk for these unhealthy statuses. METHODS: The authors included 2253 CCSs and 906 siblings from the Dutch Childhood Cancer Survivor Study-Late Effects After Childhood Cancer cohort, part 1, and added data from the Dutch general population. Questionnaire data were collected on overweight and obesity (body mass index >25.0 kg/m2), meeting physical activity guidelines (>150 minutes per week of moderate or vigorous exercises), excessive alcohol consumption (>14 and >21 alcoholic consumptions per week for women and men, respectively), daily smoking, and monthly drug use. Multivariable logistic regression analyses and two-step cluster analyses were performed to examine sociodemographic-related, health-related, cancer-related, and treatment-related associated factors of unhealthy lifestyle behaviors and to identify subgroups of CCSs at risk for multiple unhealthy behaviors. RESULTS: CCSs more often did not meet physical activity guidelines than their siblings (30.0% vs. 19.3%; p < .001). Married as marital status, lower education level, nonstudent status, and comorbidities were common associated factors for a body mass index ≥25.0 kg/m2 and insufficient physical activity, whereas male sex and lower education were shared associated factors for excessive alcohol consumption, daily smoking, and monthly drug use. A subgroup of CCSs was identified as excessive alcohol consumers, daily smokers, and monthly drug users. CONCLUSIONS: The current results emphasize the factors associated with unhealthy behaviors and the potential identification of CCSs who exhibit multiple unhealthy lifestyle behaviors.

Twisted-plywood-like tissue formation in vitro. Does curvature do the twist?

Little is known about the contribution of 3D surface geometry to the development of multilayered tissues containing fibrous extracellular matrix components, such as those found in bone. In this study, we elucidate the role of curvature in the formation of chiral, twisted-plywood-like structures. Tissues consisting of murine preosteoblast cells (MC3T3-E1) were grown on 3D scaffolds with constant-mean curvature and negative Gaussian curvature for up to 32 days. Using 3D fluorescence microscopy, the influence of surface curvature on actin stress-fiber alignment and chirality was investigated. To gain mechanistic insights, we did experiments with MC3T3-E1 cells deficient in nuclear A-type lamins or treated with drugs targeting cytoskeleton proteins. We find that wild-type cells form a thick tissue with fibers predominantly aligned along directions of negative curvature, but exhibiting a twist in orientation with respect to older tissues. Fiber orientation is conserved below the tissue surface, thus creating a twisted-plywood-like material. We further show that this alignment pattern strongly depends on the structural components of the cells (A-type lamins, actin, and myosin), showing a role of mechanosensing on tissue organization. Our data indicate the importance of substrate curvature in the formation of 3D tissues and provide insights into the emergence of chirality.

A Decision-oriented Approach to Evaluating a Leadership Curriculum in Fellowship.

Background: Graduate Medical Education (GME) emphasizes the role of the annual program evaluation to identify opportunities, create action plans, and track improvements longitudinally. There is a lack of a systematic approach to the evaluation of educational curricula. Comprehensive curriculum evaluation can inform the educators about specific modifications to achieve high standards, desired outcomes, and the anticipated objectives. Objective: To evaluate a leadership in quality improvement program in a pulmonary/critical care fellowship training program using the context, input, process, product (CIPP) model. The CIPP model, given its focus on evaluating different aspects of a program, provides concrete and targeted feedback to guide improvement decisions. Methods: Evaluation questions addressing the four focused areas were created, pilot tested, and revised. The questions were framed toward optimization of alignment (e.g., program activities with stated objectives, program goals with theoretical perspective, program curriculum with trainee needs) and gaining information about the efficacy of the program in achieving the desired outcomes. To enhance the validity of the results, we triangulated the data-gathering approach by administering surveys and conducting interviews and focus groups by random selection from the eligible participants. Qualitative data were transcribed, coded, and categorized into themes aligning with the four aspects of the CIPP model. Results: We interviewed 9 participants and conducted three focus groups with 20 participants. The surveys provided vital quantitative information that was cross-verified with the qualitative data; 23 of the 25 (92%) participants completed the survey. The results of qualitative thematic analysis were organized in the CIPP format. The context evaluation of the program revealed that the fellows and faculty were unfamiliar with the guiding principles of the course. The input evaluation highlighted the competing interests that hampered the engagement of the fellows during the evening weekly report-outs. The process evaluation revealed clustering of didactic sessions at the start of the course. The product evaluation stressed the difficulty in completing the quality improvement projects in the allotted timeframe. Conclusion: Conducting a robust evaluation of an educational curriculum provides insights into gaps in the various stages of the program. Time and resources needed for conducting evaluation by using the CIPP model should be considered.

Corrigendum: 3D organ-on-a-chip: the convergence of microphysiological systems and organoids.

[This corrects the article DOI: 10.3389/fcell.2022.1043117.].

Geodiversity in the Amazon drainage basin.

The Amazon is the largest drainage basin on Earth and contains a wide variety of abiotic landscape features. In spite of this, the geodiversity in this basin has not yet been objectively evaluated. We address this knowledge gap by combining a meta-analysis of an existing global geodiversity map and its components with a systematic literature review, to identify the key characteristics of geodiversity in the Amazon drainage basin (ADB). We also evaluate how these global geodiversity component maps, that are based on the geology, geomorphology, soils and hydrology, could be refined to better reflect geodiversity in the basin. Our review shows that geology-through lithological diversity and geological structures-and hydrology-through hydrological processes that influence geomorphology and soil diversity-are the main determinants of geodiversity. Based on these features, the ADB can be subdivided into three principal regions: (i) the Andean orogenic belt and western Amazon, (ii) the cratons and eastern Amazon, and (iii) the Solimões-Amazon river system. Additional methods to map geomorphological and hydrological diversity have been identified. Future research should focus on investigating the relationship between the geodiversity components and assess their relationship with biodiversity. Such knowledge can enhance conservation plans for the ADB. This article is part of the Theo Murphy meeting issue 'Geodiversity for science and society'.

Risk of subsequent gliomas and meningiomas among 69,460 5-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study.

BACKGROUND: Childhood cancer survivors are at risk of subsequent gliomas and meningiomas, but the risks beyond age 40 years are uncertain. We quantified these risks in the largest ever cohort. METHODS: Using data from 69,460 5-year childhood cancer survivors (diagnosed 1940-2008), across Europe, standardized incidence ratios (SIRs) and cumulative incidence were calculated. RESULTS: In total, 279 glioma and 761 meningioma were identified. CNS tumour (SIR: 16.2, 95% CI: 13.7, 19.2) and leukaemia (SIR: 11.2, 95% CI: 8.8, 14.2) survivors were at greatest risk of glioma. The SIR for CNS tumour survivors was still 4.3-fold after age 50 (95% CI: 1.9, 9.6), and for leukaemia survivors still 10.2-fold after age 40 (95% CI: 4.9, 21.4). Following cranial radiotherapy (CRT), the cumulative incidence of a glioma in CNS tumour survivors was 2.7%, 3.7% and 5.0% by ages 40, 50 and 60, respectively, whilst for leukaemia this was 1.2% and 1.7% by ages 40 and 50. The cumulative incidence of a meningioma after CRT in CNS tumour survivors doubled from 5.9% to 12.5% between ages 40 and 60, and in leukaemia survivors increased from 5.8% to 10.2% between ages 40 and 50. DISCUSSION: Clinicians following up survivors should be aware that the substantial risks of meningioma and glioma following CRT are sustained beyond age 40 and be vigilant for symptoms.

Thrombosis recurrence and major bleeding in non-anticoagulated thrombotic antiphospholipid syndrome patients: Prospective study from antiphospholipid syndrome alliance for clinical trials and international networking (APS ACTION) clinical database and repository ("Registry").

BACKGROUND: Long-term anticoagulant therapy is generally recommended for thrombotic antiphospholipid syndrome (TAPS) patients, however it may be withdrawn or not introduced in routine practice. OBJECTIVES: To prospectively evaluate the risk of thrombosis recurrence and major bleeding in non-anticoagulated TAPS patients, compared to anticoagulated TAPS, and secondly, to identify different features between those two groups. PATIENTS/METHODS: Using an international registry, we identified non-anticoagulated TAPS patients at baseline, and matched them with anticoagulated TAPS patients based on gender, age, type of previous thrombosis, and associated autoimmune disease. Thrombosis recurrence and major bleeding were prospectively analyzed using Kaplan-Meier method and compared using a marginal Cox's regression model. RESULTS: As of June 2022, 94 (14 %) of the 662 TAPS patients were not anticoagulated; and 93 of them were matched with 181 anticoagulated TAPS patients (median follow-up 5 years [interquartile range 3 to 8]). The 5-year thrombosis recurrence and major bleeding rates were 12 % versus 10 %, and 6 % versus 7 %, respectively (hazard ratio [HR] 1.38, 95 % confidence interval [CI] 0.53 to 3.56, p = 0.50 and HR 0.53; 95 % CI 0.15 to 1.86; p = 0.32, respectively). Non-anticoagulated patients were more likely to receive antiplatelet therapy (p < 0.001), and less likely to have more than one previous thrombosis (p < 0.001) and lupus anticoagulant positivity (p = 0.01). CONCLUSION: Fourteen percent of the TAPS patients were not anticoagulated at recruitment. Their recurrent thrombosis risk did not differ compared to matched anticoagulated TAPS patients, supporting the pressing need for risk-stratified secondary thrombosis prevention trials in APS investigating strategies other than anticoagulation.

Graded Replacement of Carbohydrate-Rich Breakfast Products with Dairy Products: Effects on Postprandial Aminoacidemia, Glycemic Control, Bone Metabolism, and Satiety.

BACKGROUND: Postprandial metabolic responses following dairy consumption have mostly been studied using stand-alone dairy products or milk-derived nutrients. OBJECTIVE: Assessing the impact of ingesting dairy products as part of a common breakfast on postprandial aminoacidemia, glycemic control, markers of bone metabolism, and satiety. METHODS: In this randomized, crossover study, 20 healthy young males and females consumed on 3 separate occasions an iso-energetic breakfast containing no dairy (NO-D), 1 dairy (ONE-D), or 2 dairy (TWO-D) products. Postprandial concentrations of amino acids, glucose, insulin, glucagon-like peptide-1 (GLP-1), calcium, parathyroid hormone (PTH), and markers of bone formation (P1NP) and resorption (CTX-I) were measured before and up to 300 min after initiating the breakfast, along with VAS-scales to assess satiety. RESULTS: Plasma essential and branched-chained amino acids availability (expressed as total area under the curve (tAUC)) increased in a dose-dependent manner (P<0.05 for all comparisons). Plasma glucose tAUCs were lower in ONE-D and TWO-D compared with NO-D (P<0.05 for both comparisons). Plasma GLP-1 tAUC increased in a dose-dependent manner (P<0.05 for all comparisons), whereas no differences were observed in plasma insulin tAUC between conditions (P>0.05 for all comparisons). Serum calcium tAUCs were higher in ONE-D and TWO-D compared with NO-D (P<0.05 for both comparisons), along with lower PTH tAUCs in ONE-D and TWO-D compared with NO-D (P=0.001 for both comparisons). In accordance, serum CTX-I concentrations were lower in the late postprandial period in ONE-D and TWO-D compared with NO-D (P<0.01 for both comparisons). No differences were observed in P1NP tAUCs between conditions (P>0.05). The tAUC for satiety was higher in TWO-D compared with NO-D and ONE-D (P<0.05 for both comparisons). CONCLUSIONS: Iso-energetic replacement of a carbohydrate-rich breakfast component with one serving of dairy improves postprandial amino acid availability, glycemic control, and bone metabolism. Adding a second serving of dairy in lieu of carbohydrates augments postprandial amino acid and GLP-1 concentrations while further promoting satiety. This study was registered at https://doi.org/10.1186/ISRCTN13531586 with Clinical Trial Registry number ISRCTN13531586.

Reproductive outcomes and reproductive health care utilization among male survivors of childhood cancer: A DCCSS-LATER study.

BACKGROUND: Treatment-related gonadal dysfunction leading to fertility problems is a frequently encountered late effect in childhood cancer survivors (CCSs). This study evaluated reproductive outcomes and reproductive health care utilization among male CCSs compared with male siblings. METHODS: A nationwide cohort study was conducted as part of the Dutch Childhood Cancer Survivor LATER study part 1, a questionnaire and linkage study. A questionnaire addressing reproductive outcomes and reproductive health care was completed by 1317 male CCSs and 407 male siblings. A total of 491 CCSs and 185 siblings had a previous or current desire for children and were included in this study. RESULTS: Fewer CCSs had biological children compared with siblings (65% vs. 88%; p < .001). The type of conception by men who fathered a child was comparable between CCSs and siblings (spontaneous conception of 90% of both groups; p = .86). The percentage of men who had consulted a reproductive specialist because of not siring a pregnancy was higher in CCSs compared with siblings (34% vs. 12%; p < .001). Following consultation, fewer CCSs underwent assisted reproductive techniques (ART) compared with siblings (41% vs. 77%; p = .001). After ART, fewer CCSs fathered a child compared with siblings (49% vs. 94%; p = .001). CONCLUSIONS: More male survivors consult a reproductive specialist, but fewer survivors undergo ART and father a child after ART compared with siblings. This insight is important for understanding potential problems faced by survivors regarding family planning and emphasizes the importance of collaboration between oncologists and reproductive specialists.

Cumulative Absolute Risk of Subsequent Colorectal Cancer After Abdominopelvic Radiotherapy Among Childhood Cancer Survivors: A PanCareSurFup Study.

PURPOSE: Childhood cancer survivors are at the risk of developing subsequent colorectal cancers (CRCs), but the absolute risks by treatment modality are uncertain. We quantified the absolute risks by radiotherapy treatment characteristics using clinically accessible data from a Pan-European wide case-control study nested within a large cohort of childhood cancer survivors: the PanCareSurFup Study. METHODS: Odds ratios (ORs) from a case-control study comprising 143 CRC cases and 143 controls nested within a cohort of 69,460 survivors were calculated. These, together with standardized incidence ratios for CRC for this cohort and European general population CRC incidence rates and survivors' mortality rates, were used to estimate cumulative absolute risks (CARs) by attained age for different categories of radiation to the abdominopelvic area. RESULTS: Overall, survivors treated with abdominopelvic radiotherapy treatment (ART) were three times more likely to develop a subsequent CRC than those who did not receive ART (OR, 3.1 [95% CI, 1.4 to 6.6]). For male survivors treated with ART, the CAR was 0.27% (95% CI, 0.17 to 0.59) by age 40 years, 1.08% (95% CI, 0.69 to 2.34) by age 50 years (0.27% expected in the general population), and 3.7% (95% CI, 2.36 to 7.80) by age 60 years (0.95% expected). For female survivors treated with ART, the CAR was 0.29% (95% CI, 0.18 to 0.62) by age 40 years, 1.03% (95% CI, 0.65 to 2.22) by age 50 years (0.27% expected), and 3.0% (95% CI, 1.91 to 6.37) by age 60 years (0.82% expected). CONCLUSION: We demonstrated that by age 40 years survivors of childhood cancer treated with ART already have a similar risk of CRC as those age 50 years in the general population for whom population-based CRC screening begins in many countries. This information should be used in the development of survivorship guidelines for the risk stratification of survivors concerning CRC risk.

Curli Amyloid Fibers in Escherichia coli Biofilms: The Influence of Water Availability on their Structure and Functional Properties.

Escherichia coli biofilms consist of bacteria embedded in a self-produced matrix mainly made of protein fibers and polysaccharides. The curli amyloid fibers found in the biofilm matrix are promising versatile building blocks to design sustainable bio-sourced materials. To exploit this potential, it is crucial to understand i) how environmental cues during biofilm growth influence the molecular structure of these amyloid fibers, and ii) how this translates at higher length scales. To explore these questions, the effect of water availability during biofilm growth on the conformation and functions of curli is studied. Microscopy and spectroscopy are used to characterize the amyloid fibers purified from biofilms grown on nutritive substrates with different water contents, and micro-indentation to measure the rigidity of the respective biofilms. The purified curli amyloid fibers present differences in the yield, structure, and functional properties upon biofilm growth conditions. Fiber packing and ß-sheets content correlate with their hydrophobicity and chemical stability, and with the rigidity of the biofilms. This study highlights how E. coli biofilm growth conditions impact curli structure and functions contributing to macroscopic materials properties. These fundamental findings infer an alternative strategy to tune curli structure, which will ultimately benefit engineering hierarchical and functional curli-based materials.