Paternal age and first trimester placental size and growth: The Rotterdam Periconceptional Cohort.

INTRODUCTION: Despite a noticeable trend of delayed fatherhood, less is known about the impact of paternal age on the paternally programmed placenta. We hypothesize that paternal aging affects seminal quality and as such induces ageing-related epigenetic alterations that influence placental growth. Our main aim is to investigate associations between paternal age and first trimester (vascular) placental growth trajectories. METHODS: Pregnant women were enrolled before 10 weeks of gestation in the Rotterdam Periconceptional Cohort (Predict study). Placental volumes (PV) and utero-placental vascular volumes (uPVV) were measured at 7, 9, and 11 weeks gestation. Associations between paternal age and PV and uPVV were investigated using linear mixed models and the maximum likelihood ratio test to test non-linear relationships. We adjusted for gestational age, fetal sex, parental smoking and maternal age, BMI, education and parity, and stratified for conception mode. RESULTS: From 808 pregnancies we obtained 1313 PV and from 183 pregnancies 345 uPVV measurements. We show no associations between paternal age and PV (p = 0.934) and uPVV (p = 0.489) in our total population or in pregnancies conceived naturally (PV p = 0.166; uPVV p = 0.446) and after IVF/ICSI (PV p = 0.909; uPVV p = 0.749). For example, PV was 0.9% smaller (95% CI -5.7%-7.1%) in fathers aged 40 compared to 30 years old at 9 weeks gestation in the total study population. DISCUSSION: We are not demonstrating a significant impact of paternal age on first trimester placental growth in a tertiary care population. Given the trend of increasing paternal age, our study should be repeated in the general population.

[The six dimensions of positive health valued by different stakeholders within mental health care]. / De waardering van de zes dimensies van positieve gezondheid in de ggz.

BACKGROUND: In recent years a new concept of health, 'positive health', has been developed, which focusses on a person's resilience instead of merely the absence of disease. A previous survey among a variety of stakeholders in general health care showed that there are differences in how dimensions of positive health are valued. Patients valued the spiritual and societal participation dimension higher than physicians and policymakers. AIM: To investigate how the six dimensions of positive health are valued by patients, health care professionals and policymakers in mental health care in the Netherlands, and to test whether these values differ from such stakeholders in general healthcare. METHOD: In a cross-sectional survey patients (N= 458), healthcare professionals (N=250) and policy makers (N=47) of two mental health care institutions in the Netherlands filled in an online survey. The results were compared to the results of the study by Huber e.a. (2016) by ANCOVA, paired T-tests and cohens' d. RESULTS: Respondents valued all dimensions equally high. No significant differences between groups were found, except for a significant difference on daily functioning. Patients rated this dimension significantly higher than other stakeholders. The equal significance of the six dimensions is in contrast with the findings of a previous survey among stakeholders in general health care. CONCLUSION: In contrast to stakeholders in general health care, those in mental health care valued all dimensions of health of equal and high importance. Only daily functioning was rated lower by professionals and policymakers than by patients.

The effects of antidiabetic agents on heart failure.

In the Netherlands, approximately 250,000 people are living with heart failure. About one-third of them have comorbid diabetes mellitus type 2. Until recently, the effects of antidiabetic agents on heart failure were largely unknown. This changed after an observed increased risk of heart failure and ischaemic heart disease associated with thiazolidinediones that prompted the requirement for cardiovascular outcome trials for new glucose-lowering drugs. In the past decade, three new classes of antidiabetic agents have become available (i.e. dipeptidyl peptidase­4 inhibitors, glucagon-like peptide­1 receptor agonists and sodium-glucose cotransporter­2 (SGLT2) inhibitors). Although the first two classes demonstrated no beneficial effects on heart failure compared to placebo in patients with diabetes mellitus type 2, SGLT2 inhibitors significantly and consistently lowered the risk of incident and worsening heart failure. Two recent trials indicated that these favourable effects were also present in non-diabetic patients with heart failure with reduced ejection fraction, resulting in significantly lower risks of hospitalisation for heart failure and presumably also cardiovascular and all-cause mortality. SGLT2 inhibitors have been shown to be benefit on top of recommended heart failure therapy including sacubitril/valsartan and may also prove beneficial for heart failure with preserved ejection fraction. In this review, we discuss the effects of antidiabetic agents on heart failure.

Baby's first bites: Association between observed maternal feeding behavior and infant vegetable intake and liking.

Positive experiences with the introduction of solid food in infancy may lead to positive associations with feeding in both parent and infant. During this transitional period, parental feeding behavior and infant eating behavior might mutually reinforce each other. A feeding style that is found to be associated with positive child eating behavior, is sensitive feeding. In the present study we tested bidirectional prospective relations between mother and infant behavior in a cross-lagged model using observations of two feeds on two consecutive days on which the first bites of solid food were offered. The sample consisted of 246 first-time mothers and their infants, whose feeding interactions were videotaped during two home visits. Maternal sensitive feeding behavior (consisting of responsiveness to child feeding cues, general sensitivity and non-intrusiveness) and maternal positive and negative affect were coded. In addition, infant vegetable intake was weighed and vegetable liking was reported by mother. Results showed at least some stability of maternal feeding behavior and infant vegetable intake and liking from the first to the second feed. In addition, during the second feed maternal sensitive feeding and positive affect were associated with infant vegetable intake (r=.34 and r=.14) and liking (r=.33 and r=.39). These associations were mostly absent during the first feed. Finally, infant vegetable liking during the first feed positively predicted maternal sensitive feeding behavior during the second feed (ß=.25), suggesting that the infant's first response might influence maternal behavior. Taken together, mother and infant seem more attuned during the second feed than during the first feed. Future studies might include multiple observations over a longer time period, or micro-coding. Such insights can inform prevention programs focusing on optimizing feeding experiences during the weaning period.

Emerging organic compounds in European groundwater.

In Europe, emerging organic compounds (EOCs) in groundwater is a growing research area. Prioritisation for monitoring EOCs in Europe was formalised in 2019 through the development of the first voluntary groundwater watch list (GWWL). Despite this, groundwater occurrence data in the peer reviewed literature for Europe has not been reviewed to date. Questions surrounding the effect, toxicity, movement in the subsurface and unsaturated zone make the process of regulating EOC use difficult. The aim in Europe is to develop a unified strategy for the classification, and prioritisation of EOCs to be monitored in groundwater. This paper compiles evidence from the recent published studies from across Europe, since 2012, when the last major literature global review of EOCs in groundwater took place. A total of 39 studies were identified for review based on specific selection criteria (geography, publication date, sample size>10, inclusion of EOCs data). Data on specific compounds, and associated meta-data, are compiled and reviewed. The two most frequently detected EOCs, carbamazepine and caffeine, occurred in groundwater at concentrations of up to 2.3 and 14.8 µg/L, respectively. The most frequently reported category of compounds were 'Pharmaceuticals'; a highly studied group with 135 compounds identified within 31 of the 39 studies. In Europe, the majority of reviewed studies (23) were at a regional scale, looking specifically at EOCs in a specific city or aquifer. The use of analytical methods is not uniform across Europe, and this inevitably influences the current assessment of EOCs in groundwater. A correlation between the number of compounds analysed for, and the number detected in groundwater highlights the need for further studies, especially larger-scale studies throughout Europe. For the development of EU and national regulation, further work is required to understand the occurrence and impacts of EOCs in groundwater throughout Europe and elsewhere.

Decreased Risk of COPD Exacerbations in Obese Patients.

Survival in chronic obstructive pulmonary disease (COPD) is enhanced in obese patients, which is called the obesity paradox. Despite some theories, the precise mechanism remains unclear. Since COPD exacerbations play a major role in COPD survival, this study aimed to stratify patients into BMI classes and investigate exacerbation frequency, time to readmission and survival in patients hospitalized with a COPD exacerbation. Therefore, patients hospitalized with an exacerbation of COPD were categorized into BMI groups using cut-offs <18.5, 25, 30 and ≥35 kg/m2 for underweight, normal, overweight, moderately obese and severely obese groups and followed for five years. A total of 604 COPD patients was included. In comparison to normal weight patients, the 5-year exacerbation frequency was significantly decreased by 34-40% in obese patients depending on the BMI group (1.83 ± 1.60 per year in the normal weight group; overweight 1.60 ± 1.41; moderately obese 1.20 ± 1.18; severely obese 1.09 ± 1.13 per year; and 1.59 ± 1.30 in the underweight group). The time to readmission was up to 1.7 times longer for moderately obese patients compared to normal weight patients (954 ± 734 versus 564 ± 660 days). The data were supported by enhanced survival in obese patients and a regression analysis showing that both time to readmission and survival were associated with BMI independent of other possible confounders. In conclusion, this study shows a 'dose dependent' reduced exacerbation frequency and an increased time to readmission in obese patients admitted to the hospital with an exacerbation of COPD.

Single-cell analysis of structural variations and complex rearrangements with tri-channel processing.

Structural variation (SV), involving deletions, duplications, inversions and translocations of DNA segments, is a major source of genetic variability in somatic cells and can dysregulate cancer-related pathways. However, discovering somatic SVs in single cells has been challenging, with copy-number-neutral and complex variants typically escaping detection. Here we describe single-cell tri-channel processing (scTRIP), a computational framework that integrates read depth, template strand and haplotype phase to comprehensively discover SVs in individual cells. We surveyed SV landscapes of 565 single cells, including transformed epithelial cells and patient-derived leukemic samples, to discover abundant SV classes, including inversions, translocations and complex DNA rearrangements. Analysis of the leukemic samples revealed four times more somatic SVs than cytogenetic karyotyping, submicroscopic copy-number alterations, oncogenic copy-neutral rearrangements and a subclonal chromothripsis event. Advancing current methods, single-cell tri-channel processing can directly measure SV mutational processes in individual cells, such as breakage-fusion-bridge cycles, facilitating studies of clonal evolution, genetic mosaicism and SV formation mechanisms, which could improve disease classification for precision medicine.

Baby's first bites: a randomized controlled trial to assess the effects of vegetable-exposure and sensitive feeding on vegetable acceptance, eating behavior and weight gain in infants and toddlers.

BACKGROUND: The start of complementary feeding in infancy plays an essential role in promoting healthy eating habits. Evidence shows that it is important what infants are offered during this first introduction of solid foods: e.g. starting exclusively with vegetables is more successful for vegetable acceptance than starting with fruits. How infants are introduced to solid foods also matters: if parents are sensitive and responsive to infant cues during feeding, this may promote self-regulation of energy intake and a healthy weight. However, the effectiveness of the what and the how of complementary feeding has never been experimentally tested in the same study. In the current project the what and how (and their combination) are tested in one study to determine their relative importance for fostering vegetable acceptance and self-regulation of energy intake in infants. METHODS: A four-arm randomized controlled trial (Baby's First Bites (BFB)) was designed for 240 first-time Dutch mothers and their infants, 60 per arm. In this trial, we compare the effectiveness of (a) a vegetable-exposure intervention focusing on the what in complementary feeding; (b) a sensitive feeding intervention focusing on the how in complementary feeding, (c) a combined intervention focusing on the what and how in complementary feeding; (d) an attention-control group. All mothers participate in five sessions spread over the first year of eating solid foods (child age 4-16 months). Primary outcomes are vegetable consumption, vegetable liking and self-regulation of energy intake. Secondary outcomes are child eating behaviors, child anthropometrics and maternal feeding behavior. Outcomes are assessed before, during and directly after the interventions (child age 18 months), and when children are 24 and 36 months old. DISCUSSION: The outcomes are expected to assess the impact of the interventions and provide new insights into the mechanisms underlying the development of vegetable acceptance, self-regulation and healthy eating patterns in infants and toddlers, as well as the prevention of overweight. The results may be used to improve current dietary advice given to parents of their young children on complementary feeding. TRIAL REGISTRATION: The trial was retrospectively registered during inclusion of participants at the Netherlands National Trial Register (identifier NTR6572 ) and at ClinicalTrials.gov ( NCT03348176 ). Protocol issue date: 1 April 2018; version number 1.

Predictors of short-term and long-term mortality in critically ill patients admitted to the intensive care unit following allogeneic stem cell transplantation.

Historically, the mortality of patients admitted to the ICU after allogeneic stem cell transplantation (alloSCT) is high. Advancements in transplantation procedures, infectious monitoring and supportive care may have improved the outcome. This study aimed to determine short-term and long-term mortality after ICU admission of patients after alloSCT and to identify prognostic clinical and transplantation-related determinants present at ICU admission for long-term outcome. A multicenter cohort study was performed to determine 30-day and 1-year mortality within 2 years following alloSCT. A total of 251 patients were included. The 30-day and 1-year mortality was 55% and 80%, respectively. Platelet count <25 × 109/L (OR: 2.26, CI: 1.02-5.01) and serum bilirubin >19 µmol/L (OR: 2.47 CI: 1.08-5.65) at admission, other donor than a HLA-matched-related or HLA-matched-unrelated donor (OR: 4.59, CI: 1.49-14.1) and vasoactive medication within 24 h (OR: 2.35, CI: 1.28-4.31) were associated with increased 30-day mortality. Other donor than a HLA-matched-related or HLA-matched-unrelated donor (OR: 1.9, CI: 1.13-3.19), serum bilirubin >77 (OR: 2.05, CI: 1.28-3.30) and vasoactive medication within 24 h (OR: 1.65, CI: 1.12-2.43) were associated with increased 1-year mortality. Neutropenia was associated with decreased 30-day and 1-year mortality (OR: 0.29, CI: 0.14-0.59 and OR: 0.70, CI: 0.48-0.98). Myeloablative conditioning and T cell-depleted transplantation were not associated with increased mortality.

Differential effects of high fat diet and diet-induced obesity on skeletal acquisition in female C57BL/6J vs. FVB/NJ Mice.

The effects of obesity on bone metabolism are complex, and may be mediated by consumption of a high fat diet and/or by obesity-induced metabolic dysregulation. To test the hypothesis that both high fat (HF) diet and diet-induced metabolic disease independently decrease skeletal acquisition, we compared effects of HF diet on bone mass and microarchitecture in two mouse strains: diet-induced obesity (DIO)-susceptible C57BL/6J (B6) and DIO-resistant FVB/NJ (FVB). At 3 wks of age we weaned 120 female FVB and B6 mice onto normal (N, 10% Kcal/fat) or HF diet (45% Kcal/fat) and euthanized them at 6, 12 and 20 weeks of age (N = 10/grp). Outcomes included body mass; percent fat and whole-body bone mineral density (WBBMD, g/cm2) via DXA; cortical and trabecular bone architecture at the midshaft and distal femur via µCT; and marrow adiposity via histomorphometry. In FVB HF, body mass, percent body fat, WBBMD and marrow adiposity did not differ vs. N, but trabecular bone mass was lower at 6 wks of age only (p < 0.05), cortical bone geometric properties were lower at 12 wks only, and bone strength was lower at 20 wks of age only in HF vs. N (p < 0.05). In contrast, B6 HF had higher body mass, percent body fat, and leptin vs. N. B6 HF also had higher WBBMD (p < 0.05) at 9 and 12 wks of age but lower distal femur trabecular bone mass at 12 wks of age, and lower body mass-adjusted cortical bone properties at 20 wks of age compared to N (p < 0.05). Marrow adiposity was also markedly higher in B6 HF vs. N. Overall, HF diet negatively affected bone mass in both strains, but was more deleterious to trabecular bone microarchitecture and marrow adiposity in B6 than in FVB mice. These data suggest that in addition to fat consumption itself, the metabolic response to high fat diet independently alters skeletal acquisition in obesity.

Endometrial thickness in women undergoing IUI with ovarian stimulation. How thick is too thin? A systematic review and meta-analysis.

STUDY QUESTION: Is pre-ovulatory endometrial thickness (EMT) in women with unexplained subfertility undergoing IUI with ovarian stimulation (OS) associated with pregnancy chances? SUMMARY ANSWER: We found no evidence for an association between EMT and pregnancy chances. WHAT IS KNOWN ALREADY: It has been suggested that OS with clomiphene citrate (CC) results in a lower EMT than with gonadotrophins or aromatase inhibitors, but the clinical consequences in terms of pregnancy are unclear. STUDY DESIGN, SIZE, DURATION: We performed a systematic review and meta-analysis of studies comparing CC, gonadotrophins or aromatase inhibitors in an IUI program reporting on EMT and pregnancy rates in women with unexplained subfertility. PARTICIPANTS/MATERIALS, SETTING, METHODS: We searched MEDLINE, EMBASE and the non-MEDLINE subset of PubMed from inception to 28th June 2016 and cross-checked references of relevant articles. Outcome measures were clinical pregnancy rate and mean pre-ovulatory EMT. We calculated mean differences (MD) with 95% CIs with a fixed effect model, and in case of heterogeneity with an I2 > 50% a random effect model. We performed a meta-regression analysis to determine if stimulating drugs interacted with the estimated effect of EMT. MAIN RESULTS AND THE ROLE OF CHANCE: Our search retrieved 1563 articles of which 23 were included, totaling 3846 women. There were 17 RCTs and 6 cohort studies. The average study quality was low and there was considerable to substantial statistical heterogeneity. Seven studies provided data on EMT in relation to pregnancy. There was no evidence of a difference in EMT between women who conceived and women that did not conceive (1525 women, MDrandom: 0.51 mm, 95% CI: -0.05 to 1.07). Women treated with CC had a significantly thinner EMT than women treated with gonadotrophins (two studies, MD: -0.33, 95% CI: -0.64 to -0.01). There was no evidence of a difference in EMT when comparing CC with letrozole (five studies, MDrandom: -0.84, 95% CI: -1.97 to 0.28). The combination of CC plus gonadotrophins resulted in a slightly thinner endometrium than letrozole (nine studies, MDrandom: -0.79, 95% CI: -1.37 to -0.20). Letrozole resulted in a thinner EMT than gonadotrophins (two studies, MDrandom: -1.31, 95% CI: -2.08 to -0.53). LIMITATIONS, REASONS FOR CAUTION: The overall quality of the included studies was low to moderate. We found considerable to substantial heterogeneity in the comparisons, hampering firm conclusions. WIDER IMPLICATIONS OF THE FINDINGS: We found no evidence for an association between EMT and pregnancy rates during IUI -OS. As a consequence, canceling IUI cycles because of a thin endometrial lining may negatively affect clinical care. Although we found some evidence for very small differences in EMT when comparing various drugs, we cannot make inferences on their effect on pregnancy chances since these differences may be coincidental. STUDY FUNDING/COMPETING INTEREST(S): None. REGISTRATION NUMBER: N/A.

Sclerostin antibody inhibits skeletal deterioration in mice exposed to partial weight-bearing.

Whereas much is known regarding the musculoskeletal responses to full unloading, little is known about the physiological effects and response to pharmacological agents in partial unloading (e.g. Moon and Mars) environments. To address this, we used a previously developed ground-based model of partial weight-bearing (PWB) that allows chronic exposure to reduced weight-bearing in mice to determine the effects of murine sclerostin antibody (SclAbII) on bone microstructure and strength across different levels of mechanical unloading. We hypothesize that treatment with SclAbII would improve bone mass, microarchitecture and strength in all loading conditions, but that there would be a greater skeletal response in the normally loaded mice than in partially unloaded mice suggesting the importance of combined countermeasures for exploration-class long duration spaceflight missions. Eleven-week-old female mice were assigned to one of four loading groups: normal weight-bearing controls (CON) or weight-bearing at 20% (PWB20), 40% (PWB40) or 70% (PWB70) of normal. Mice in each group received either SclAbII (25mg/kg) or vehicle (VEH) via twice weekly subcutaneous injection for 3 weeks. In partially-unloaded VEH-treated groups, leg BMD decreased -5 to -10% in a load-dependent manner. SclAbII treatment completely inhibited bone deterioration due to PWB, with bone properties in SclAbII-treated groups being equal to or greater than those of CON, VEH-treated mice. SclAbII treatment increased leg BMD from +14 to +18% in the PWB groups and 30 ± 3% in CON (p< 0.0001 for all). Trabecular bone volume, assessed by µCT at the distal femur, was lower in all partially unloaded VEH-treated groups vs. CON-VEH (p< 0.05), and was 2-3 fold higher in SclAbII-treated groups (p< 0.001). Midshaft femoral strength was also significantly higher in SclAbII vs. VEH-groups in all-loading conditions. These results suggest that greater weight bearing leads to greater benefits of SclAbII on bone mass, particularly in the trabecular compartment. Altogether, these results demonstrate the efficacy of sclerostin antibody therapy in preventing astronaut bone loss during terrestrial solar system exploration.

Towards a 'patient-centred' operationalisation of the new dynamic concept of health: a mixed methods study.

OBJECTIVE: To evaluate among stakeholders the support for the new, dynamic concept of health, as published in 2011: 'Health as the ability to adapt and to self-manage', and to elaborate perceived indicators of health in order to make the concept measurable. DESIGN: A mixed methods study: a qualitative first step with interviews and focus groups, followed by a quantitative survey. PARTICIPANTS: Representatives of seven healthcare stakeholder domains, for example, healthcare providers, patients with a chronic condition and policymakers. The qualitative study involved 140 stakeholders; the survey 1938 participants. RESULTS: The new concept was appreciated, as it addresses people as more than their illness and focuses on strengths rather than weaknesses. Caution is needed as the concept requires substantial personal input of which not everyone is capable. The qualitative study identified 556 health indicators, categorised into six dimensions: bodily functions, mental functions and perception, spiritual/existential dimension, quality of life, social and societal participation, and daily functioning, with 32 underlying aspects. The quantitative study showed all stakeholder groups considering bodily functions to represent health, whereas for other dimensions there were significant differences between groups. Patients considered all six dimensions almost equally important, thus preferring a broad concept of health, whereas physicians assessed health more narrowly and biomedically. In the qualitative study, 78% of respondents considered their health indicators to represent the concept. CONCLUSIONS: To prevent confusion with health as 'absence of disease', we propose the use of the term 'positive health' for the broad perception of health with six dimensions, as preferred by patients. This broad perception deserves attention by healthcare providers as it may support shared decision-making in medical practice. For policymakers, the broad perception of 'positive health' is valuable as it bridges the gap between healthcare and the social domain, and by that it may demedicalise societal problems.

Bloodstream infections during the onset of necrotizing enterocolitis and their relation with the pro-inflammatory response, gut wall integrity and severity of disease in NEC.

INTRODUCTION: Bacterial involvement is believed to play a pivotal role in the development and disease outcome of NEC. However, whether a bloodstream infection (BSI) predisposes to NEC (e.g. by activating the pro-inflammatory response) or result from the loss of gut wall integrity during NEC development is a longstanding question. OBJECTIVE: We hypothesize that the occurrence of a BSI plays a complementary role in the pathogenesis of NEC. The first aim of the study was to correlate the occurrence of a BSI during the early phase of NEC with intestinal fatty acid-binding protein (I-FABP) levels, as a marker for loss of gut wall integrity owing to mucosal damage, and Interleukin (IL)-8 levels, as a biomarker for the pro-inflammatory cascade in NEC. The second aim of the study was to investigate the relation between the occurrence of a BSI and disease outcome. MATERIAL AND METHODS: We combined data from prospective trials from two large academic pediatric surgical centers. Thirty-eight neonates with NEC, 5 neonates with bacterial sepsis, and 14 controls were included. RESULTS: BSIs occurred in 10/38 (26%) neonates at NEC onset. No association between the occurrence of BSIs and I-FABP levels in plasma (cohort 1: median 11ng/mL (range 0.8-298), cohort 2: median 6.8ng/mL (range 1.3-15)) was found in NEC patients (cohort 1: p=0.41; cohort 2: p=0.90). In addition, the occurrence of BSIs did not correlate with IL-8 (median 1562pg/mL (range 150-7,500); p=0.99). While the occurrence of a BSI was not correlated with Bell's stage (p=0.85), mortality was higher in patients with a BSI (p=0.005). CONCLUSION: The low incidence of BSIs and the absent association of both the markers for loss of gut wall integrity and the pro-inflammatory response during the early phase of NEC, support the hypothesis that the presence of a BSI does not precede NEC.

Early-onset type 2 diabetes impairs skeletal acquisition in the male TALLYHO/JngJ mouse.

Type 2 diabetes (T2D) incidence in adolescents is rising and may interfere with peak bone mass acquisition. We tested the effects of early-onset T2D on bone mass, microarchitecture, and strength in the TALLYHO/JngJ mouse, which develops T2D by 8 weeks of age. We assessed metabolism and skeletal acquisition in male TALLYHO/JngJ and SWR/J controls (n = 8-10/group) from 4 weeks to 8 and 17 weeks of age. Tallyho mice were obese; had an approximately 2-fold higher leptin and percentage body fat; and had lower bone mineral density vs SWR at all time points (P < .03 for all). Tallyho had severe deficits in distal femur trabecular bone volume fraction (-54%), trabecular number (-27%), and connectivity density (-82%) (P < .01 for all). Bone formation was higher in Tallyho mice at 8 weeks but lower by 17 weeks of age vs SWR despite similar numbers of osteoblasts. Bone marrow adiposity was 7- to 50-fold higher in Tallyho vs SWR. In vitro, primary bone marrow stromal cell differentiation into osteoblast and adipocyte lineages was similar in SWR and Tallyho, suggesting skeletal deficits were not due to intrinsic defects in Tallyho bone-forming cells. These data suggest the Tallyho mouse might be a useful model to study the skeletal effects of adolescent T2D.

Trends in the outcomes of Dutch haematological patients receiving intensive care support.

BACKGROUND: Because of the assumed dismal prognosis there is still reluctance to admit haematological patients to the intensive care unit (ICU). This study was conducted to determine trends in outcome of allogeneic haematopoietic stem cell transplant (HSCT) recipients transferred to the intensive care unit in a Dutch tertiary care hospital. METHODS: All patients who received allogeneic HSCT between 2004-2010 were included in the analyses. Baseline and outcome characteristics were compared and risk factors for ICU admission and survival were identified. Changes in outcome over time of three cohorts of HSCT recipients were investigated. RESULTS: Of 319 consecutive HSCT recipients, 49 (15%) were transferred to the ICU for a median (IQR) of 10 (6-45) days following their transplantation, of whom 43% were severely neutropenic and 90% had received systemic immunosuppressive therapy for graft-versus-host disease prophylaxis. Univariate logistic regression showed that transplantation from an unrelated donor and myeloablative conditioning were significant risk factors for ICU admission. Prolonged use of vasopressors, invasive mechanical ventilation and male gender were significant predictors for ICU mortality, while neutropenia and graft-versus-host disease were not. Over the years, APACHE-II severity of illness scores remained unchanged (21.0±7.1, 20.1±5.6, 21.2±6.6), while 100-day post-transplant mortality of patients who had been transferred to the ICU decreased significantly from 78% (2004÷2005) to 57% (2006÷2007), and 35% (2008÷2009). CONCLUSIONS: While for allogeneic HSCT patients the severity of illness on admission to the ICU did not change, the 100-day post-transplant survival improved. These data indicate that reluctance to submit haematological patients to the ICU is not warranted.

Incidence of and risk factors for persistent gram-positive bacteraemia and catheter-related thrombosis in haematopoietic stem cell transplantation.

A cohort of 439 haematopoietic SCT recipients was analysed to determine the incidence of Gram-positive coccal bacteraemia and thromboembolic events associated with the use of central venous catheters (CVCs) and to determine risk factors for these complications. The incidences of persistent coagulase-negative staphylococcal (CoNS) bacteraemia, symptomatic thrombosis and thrombophlebitis were 25%, 9.6% and 6.6%, respectively. Duration of neutropenia (in days, odds ratio (OR) 1.02; P=0.04) and left-sided placement of the CVCs (OR 1.73; P=0.03) were independent risk factors for the occurrence of persistent CoNS bacteraemia, whereas the use of less mucotoxic conditioning regimens was associated with a lower risk (high-dose melphalan (HDM)/BEAM vs other regimens, OR 0.24; P<0.001). Use of TBI, persistent CoNS bacteraemia and tip colonisation were all significantly associated with an increased risk of symptomatic thrombosis (OR 6.03, 3.36 and 2.80, respectively; P0.02). The risk factors found in this cohort of SCT recipients differed from those found in the general cancer population, showing an important role for persisting bacteraemia in the pathogenesis of CVC-associated thrombosis. Therefore, we constructed a new algorithm in order to improve catheter management and prevent these CVC-related complications.

Snowmelt contributions to discharge of the Ganges.

Himalayan headwaters supply large quantities of runoff derived from snowmelt and monsoon rainfall to the Ganges River. Actual snowmelt contribution to discharge in the Ganges remains conjectural under both present and future climatic conditions. As snowmelt is likely to be perturbed through climatic warming, four hydrological models, VIC, JULES, LPJmL and SWAT, appropriate for coupling with regional climate models, were used to provide a baseline estimate of snowmelt contribution to flow at seasonal and annual timescales. The models constrain estimates of snowmelt contributions to between 1% and 5% of overall basin runoff. Snowmelt is, however, significant in spring months, a period in which other sources of runoff are scarce.

Regional heterogeneity changes in DCE-MRI as response to isolated limb perfusion in experimental soft-tissue sarcomas.

Experimental evidence supports an association between heterogeneity in tumor perfusion and response to chemotherapy/radiotherapy, disease progression and malignancy. Therefore, changes in tumor perfusion may be used to assess early effects of tumor treatment. However, evaluating changes in tumor perfusion during treatment is complicated by extensive changes in tumor type, size, shape and appearance. Therefore, this study assesses the regional heterogeneity of tumors by dynamic contrast-enhanced MRI (DCE-MRI) and evaluates changes in response to isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan. Data were acquired in an experimental cancer model, using a macromolecular contrast medium, albumin-(Gd-DTPA)45. Small fragments of BN 175 (a soft-tissue sarcoma) were implanted in eight brown Norway rats. MRI of five drug-treated and three sham-treated rats was performed at baseline and 1 h after ILP intervention. Properly co-registered baseline and follow-up DCE-MRI were used to estimate the volume transfer constant (K(trans) ) pharmacokinetic maps. The regional heterogeneity was estimated in 16 tumor sectors and presented in cumulative map-volume histograms. On average, ILP-treated tumors showed a decrease in regional heterogeneity on the histograms. This study shows that heterogenic changes in regional tumor perfusion, estimated using DCE-MRI pharmacokinetic maps, can be measured and used to assess the short-term effects of a potentially curative treatment on the tumor microvasculature in an experimental soft-tissue sarcoma model.