The partially asymmetric zero range process with quenched disorder

We consider the one-dimensional partially asymmetric zero range process where the hopping rates as well as the easy direction of hopping are random variables. For this type of disorder there is a condensation phenomena in the thermodynamic limit: the particles typically occupy one single site and the fraction of particles outside the condensate is vanishing. We use extreme value statistics and an asymptotically exact strong disorder renormalization group method to explore the properties of the steady state. In a finite system of $L$ sites the current vanishes as $J \sim L^{-z}$, where the dynamical exponent, $z$, is exactly calculated. For $0<z<1$ the transport is realized by $N_a \sim L^{1-z}$ active particles, which move with a constant velocity, whereas for $z>1$ the transport is due to the anomalous diffusion of a single Brownian particle. Inactive particles are localized at a second special site and their number in rare realizations is macroscopic. The average density profile of inactive particles has a width of, $\xi \sim \delta^{-2}$, in terms of the asymmetry parameter, $\delta$. In addition to this, we have investigated the approach to the steady state of the system through a coarsening process and found that the size of the condensate grows as $n_L \sim t^{1/(1+z)}$ for large times. For the unbiased model $z$ is formally infinite and the coarsening is logarithmically slow.Comment: 12 pages, 9 figure

ATPγS stalls splicing after B complex formation but prior to spliceosome activation.

The ATP analog ATPγS inhibits pre-mRNA splicing in vitro, but there have been conflicting reports as to which step of splicing is inhibited by this small molecule and its inhibitory mechanism remains unclear. Here we have dissected the effect of ATPγS on pre-mRNA splicing in vitro. Addition of ATPγS to splicing extracts depleted of ATP inhibited both catalytic steps of splicing. At ATPγS concentrations ≥0.5 mM, precatalytic B complexes accumulate, demonstrating a block prior to or during the spliceosome activation stage. Affinity purification of the ATPγS-stalled B complexes (B(ATPγS)) and subsequent characterization of their abundant protein components by 2D gel electrophoresis revealed that B(ATPγS) complexes are compositionally more homogeneous than B complexes previously isolated in the presence of ATP. In particular, they contain little or no Prp19/CDC5L complex proteins, indicating that these proteins are recruited after assembly of the precatalytic spliceosome. Under the electron microscope, B(ATPγS) complexes exhibit a morphology highly similar to B complexes, indicating that the ATPγS-induced block in the transformation of the B to B(act) complex is not due to a major structural defect. Likely mechanisms whereby ATPγS blocks spliceosome assembly at the activation stage, including inhibition of the RNA helicase Brr2, are discussed. Given their more homogeneous composition, B complexes stalled by ATPγS may prove highly useful for both functional and structural analyses of the precatalytic spliceosome and its conversion into an activated B(act) spliceosomal complex

Dynamics of an exclusion process with creation and annihilation

We examine the dynamical properties of an exclusion process with creation and annihilation of particles in the framework of a phenomenological domain-wall theory, by scaling arguments and by numerical simulation. We find that the length- and time scale are finite in the maximum current phase for finite creation- and annihilation rates as opposed to the algebraically decaying correlations of the totally asymmetric simple exclusion process (TASEP). Critical exponents of the transition to the TASEP are determined. The case where bulk creation- and annihilation rates vanish faster than the inverse of the system size N is also analyzed. We point out that shock localization is possible even for rates proportional to 1/N^a, 1<a<2.Comment: 16 pages, 8 figures, typos corrected, references added, section 4 revise

Ease of use and accuracy of a perinatal measuring device (Episiometer) to ensure correct angle and length of a mediolateral episiotomy: a mixed methods study

Introduction: To guide clinicians in performing mediolateral episiotomies (MLEs) at 60‐degrees, a new clinical innovation called the 'Episiometer' was developed. The aim of this study was to assess the usability and accuracy of the Episiometer in guiding clinicians to perform a safe episiotomy in both low‐ and high‐resource settings. Design: A prospective, multi‐site Phase‐I clinical trial was conducted between January 2017 and July 2018, involving three international study sites: Australia; Papua New Guinea; and India. The study design was mixed‐methods, incorporating an explanatory sequential design using surveys, clinician interviews and patient chart review to determine the usability and accuracy of the Episiometer. The patient chart review and results of this are discussed in an accompanying article. Methods: The Episiometer is the clinical innovation designed to attain an episiotomy cutting angle of 60‐degrees. The instrument is designed to assist clinicians to make an accurate and consistent episiotomy cutting angle within a 'safe' green zone between 45–60 degrees and length of at least 4 cm. The instrument also improves the visibility of the 60‐degree line to clinicians, and provides an exact measurement for length (located on the 60‐degree angle line). Clinicians from all three sites were recruited to provide feedback and measurements of incisions performed using the Episiometer (n = 135) following attendance at a minimum of at least one training session with site coordinators. Twenty of these clinicians were then recruited randomly from the sample who responded in the surveys and interviewed face‐to‐face. Patients were followed up 6‐weeks postpartum to monitor potential complications (n = 120). Results: Overall, the Episiometer was well received by clinicians – particularly by more junior staff members who were significantly more likely to report the Episiometer as being beneficial in guiding a safe MLE compared to their more senior counterparts (P = 0.003 and P = 0.011, respectively). In addition, 89% of incisions (107/120) were within the 'safe zone' between 45‐60 degrees, and 40% (48/120) were made at exactly 60‐degrees. No patient had any degree of perineal tear at follow up. Conclusion: The Episiometer is a well‐received clinical innovation in both high‐resource and lower resource settings. When used as directed, the Episiometer produces an accurate and safe incision, and reduces variation in clinicians' performance of episiotomy

Resting energy expenditure in children at risk of hypothalamic dysfunction

Objective: Children with suprasellar brain damage are at risk of hypothalamic dysfunction (HD). HD may lead to decreased resting energy expenditure (REE). Decreased REE, however, is not present in all children with HD. Our aim was to assess which children suspect for HD have low REE, and its association with clinical severity of HD or radiological hypothalamic damage. Patients and methods: A retrospective cohort study was performed. Measured REE (mREE) of children at risk of HD was compared to predicted REE (pREE). Low REE was defined as mREE <90% of predicted. The mREE/pREE quotient was associated to a clinical score for HD symptoms and to radiological hypothalamic damage. Results: In total, 67 children at risk of HD (96% brain tumor diagnosis) with a mean BMI SDS of +2.3 ± 1.0 were included. Of these, 45 (67.2%) had low mREE. Children with severe HD had a significant lower mean mREE/pREE quotient compared to children with no, mild, or moderate HD. Mean mREE/pREE quotient of children with posterior hypothalamic damage was significantly lower compared to children with no or anterior damage. Tumor progression or tumor recurrence, severe clinical HD, and panhypopituitarism with diabetes insipidus (DI) were significant risk factors for reduced REE. Conclusion: REE may be lowered in children with hypothalamic damage and is associated to the degree of clinical HD. REE is, however, not lowered in all children suspect for HD. For children with mild or moderate clinical HD symptoms, REE measurements may be useful to distinguish between those who may benefit from obesity treatment that increases REE from those who would be better helped using other obesity interventions

Body mass index at diagnosis of a childhood brain tumor; a reflection of hypothalamic-pituitary dysfunction or lifestyle?

Purpose: Childhood brain tumor survivors (CBTS) are at risk of becoming overweight, which has been shown to be associated with hypothalamic-pituitary (HP) dysfunction during follow-up. Body mass index (BMI) at diagnosis is related to BMI at follow-up. It is uncertain, however, whether aberrant BMI at brain tumor diagnosis reflects early hypothalamic dysfunction or rather reflects genetic and sociodemographic characteristics. We aimed to examine whether BMI at childhood brain tumor diagnosis is associated with HP dysfunction at diagnosis or its development during follow-up. Methods: The association of BMI at diagnosis of a childhood brain tumor to HP dysfunction at diagnosis or during follow-up was examined in a Dutch cohort of 685 CBTS, excluding children with craniopharyngioma or a pituitary tumor. Individual patient data were retrospectively extracted from patient charts. Results: Of 685 CTBS, 4.7% were underweight, 14.2% were overweight, and 3.8% were obese at diagnosis. Being overweight or obese at diagnosis was not associated with anterior pituitary deficiency or diabetes insipidus at diagnosis or during follow-up. In children with suprasellar tumors, being obese at diagnosis was associated with central precocious puberty. Conclusion: Overweight or obesity at diagnosis of a childhood brain tumor seems not to be associated with pituitary deficiencies. These results suggest that genetics and lifestyle may be more important etiologic factors for higher BMI at diagnosis in these children than hypothalamic dysfunction. To improve the long-term outcome of CBTS with regards to overweight and obesity, more attention should be given to lifestyle already at the time of brain tumor treatment

Recommendations on Surveillance for Differentiated Thyroid Carcinoma in Children with PTEN Hamartoma Tumor Syndrome

BACKGROUND: PTEN hamartoma tumor syndrome (PHTS) represents a group of syndromes caused by a mutation in the PTEN gene. Children with a germline PTEN mutation have an increased risk of developing differentiated thyroid carcinoma (DTC). Several guidelines have focused on thyroid surveillance in these children, but studies substantiating these recommendations are lacking. OBJECTIVE: The present study intends to provide the available evidence for a thyroid carcinoma surveillance program in children with PHTS. METHODS: An extensive literature search was performed to identify all studies on DTC in pediatric PHTS patients. Two pediatric cases are presented to illustrate the pros and cons of thyroid carcinoma surveillance. Recommendations for other patient groups at risk for DTC were evaluated. Consensus within the study team on recommendations for children with PHTS was reached by balancing the incidence and behavior of DTC with the pros and cons of thyroid surveillance, and the different surveillance methods. RESULTS: In 5 cohort studies the incidence of DTC in childhood ranged from 4 to 12%. In total 57 cases of DTC and/or benign nodular disease in pediatric PHTS patients were identified, of which 27 had proven DTC, with a median age of 12 years (range 4-17). Follicular thyroid carcinoma (FTC) was diagnosed in 52% of the pediatric DTC patients. No evidence was found for a different clinical behavior of DTC in PHTS patients compared to sporadic DTC. CONCLUSIONS: Children with PHTS are at increased risk for developing DTC, with 4 years being the youngest age reported at presentation and FTC being overrepresented. DTC in pediatric PHTS patients does not seem to be more aggressive than sporadic DTC. RECOMMENDATIONS: Surveillance for DTC in pediatric PHTS patients seems justified, as early diagnosis may decrease morbidity. Consensus within the study team was reached to recommend surveillance from the age of 10 years onwards, since at that age the incidence of DTC seems to reach 5%. Surveillance for DTC should consist of yearly neck palpation and triennial thyroid ultrasound. Surveillance in children with PHTS should be performed in a center of excellence for pediatric thyroid disease or PHTS

The Dutch LATER physical outcomes set for self-reported data in survivors of childhood cancer

Purposes: Studies investigating self-reported long-term morbidity in childhood cancer survivors (CCS) are using heterogeneous outcome definitions, which compromises comparability and include (un)treated asymptomatic and symptomatic outcomes. We generated a Dutch LATER core set of clinically relevant physical outcomes, based on self-reported data. Clinically relevant outcomes were defined as outcomes associated with clinical symptoms or requiring medical treatment. Methods: First, we generated a draft outcome set based on existing questionnaires embedded in the Childhood Cancer Survivor Study, British Childhood Cancer Survivor Study, and Dutch LATER study. We added specific outcomes reported by survivors in the Dutch LATER questionnaire. Second, we selected a list of clinical relevant outcomes by agreement among a Dutch LATER experts team. Third, we compared the proposed clinically relevant outcomes to the severity grading of the Common Terminology Criteria for Adverse Events (CTCAE). Results: A core set of 74 self-reported long-term clinically relevant physical morbidity outcomes was established. Comparison to the CTCAE showed that 36% of these clinically relevant outcomes were missing in the CTCAE. Implications for Cancer Survivors: This proposed core outcome set of clinical relevant outcomes for self-reported data will be used to investigate the self-reported morbidity in the Dutch LATER study. Furthermore, this Dutch LATER outcome set can be used as a starting point for international harmonization for long-term outcomes in survivors of childhood cancer