Final State Interactions Effects in Neutrino-Nucleus Interactions

Final State Interactions effects are discussed in the context of Monte Carlo simulations of neutrino-nucleus interactions. A role of Formation Time is explained and several models describing this effect are compared. Various observables which are sensitive to FSI effects are reviewed including pion-nucleus interaction and hadron yields in backward hemisphere. NuWro Monte Carlo neutrino event generator is described and its ability to understand neutral current $\pi^0$ production data in $\sim 1$ GeV neutrino flux experiments is demonstrated.Comment: 13 pages, 16 figure

Wroclaw neutrino event generator

A neutrino event generator developed by the Wroclaw Neutrino Group is described. The physical models included in the generator are discussed and illustrated with the results of simulations. The considered processes are quasi-elastic scattering and pion production modelled by combining the $\Delta$ resonance excitation and deep inelastic scattering.Comment: Talk given at 2nd Scandanavian Neutrino Workshop (SNOW 2006), Stockholm, Sweden, 2-6 May 2006. 3 pages, 6 figure

Supplemental Iodide for Preterm Infants and Developmental Outcomes at 2 Years:an RCT

Background The recommendation for enteral iodide intake for preterm infants is 30–40 μg/kg/day and 1μg/kg/day for parenteral intake. Preterm infants are vulnerable to iodide insufficiency and thyroid dysfunction. The hypothesis tested whether, compared to placebo, iodide supplementation of preterm infants improves neurodevelopment. Methods A randomized controlled trial of iodide supplementation versus placebo in infants <31 weeks’ gestation. Trial solutions (sodium iodide or sodium chloride; dose 30μg/kg/day) were given within 42 hours of birth to the equivalent of 34 weeks’ gestation. The only exclusion criterion was maternal iodide exposure during pregnancy or delivery. Whole blood levels of thyroxine, thyrotropin and thyroid binding globulin were measured on four specific postnatal days. The primary outcome was neurodevelopmental status at two years’ of age, measured using the Bayley-III scales. The primary analyses are by intention-to-treat and data are presented also for survivors. Results 1,273 infants (637 intervention, 636 placebo) were recruited from 21 UK neonatal units. 131 infants died, and neurodevelopmental assessments were undertaken in 498 iodide and 499 placebo supplemented infants. There were no significant differences between the intervention and placebo groups in the primary outcome: mean difference Cognitive score, -0.34, 95% confidence interval (CI) -2.57 to 1.89; Motor composite score, 0.21, 95% CI -2.23 to 2.65; Language composite score, -0.05, 95%CI -2.48 to 2.39. There was evidence of weak interaction between iodide supplementation and hypothyroxinemic status in the Language composite score and one subtest score. Conclusions Overall iodide supplementation provided no benefit to neurodevelopment measured at 2 years of age

Homozygous Hypomorphic HNF1A Alleles Are a Novel Cause of Young-Onset Diabetes and Result in Sulfonylurea-Sensitive Diabetes

Objective: Heterozygous loss-of-function mutations in HNF1A cause maturity-onset diabetes of the young (MODY). Affected individuals can be treated with low-dose sulfonylureas. Individuals with homozygous HNF1A mutations causing MODY have not been reported. Research design and methods: We phenotyped a kindred with young-onset diabetes and performed molecular genetic testing, a mixed meal tolerance test, a sulfonylurea challenge, and in vitro assays to assess variant protein function. Results: A homozygous HNF1A variant (p.A251T) was identified in three insulin-treated family members diagnosed with diabetes before 20 years of age. Those with the homozygous variant had low hs-CRP levels (0.2-0.8 mg/L), and those tested demonstrated sensitivity to sulfonylurea given at a low dose, completely transitioning off insulin. In silico modeling predicted a variant of unknown significance; however, in vitro studies supported a modest reduction in transactivation potential (79% of that for the wild type; P < 0.05) in the absence of endogenous HNF1A. Conclusions: Homozygous hypomorphic HNF1A variants are a cause of HNF1A-MODY. We thus expand the allelic spectrum of variants in dominant genes causing diabetes.This article is freely available via Open Access. Click on the publisher URL to access it via the publisher's site.This work was undertaken with funds from the Diabetes Research & Wellness Foundation (through a Sutherland-Earl Fellowship 2013–2016) and the Imperial College Healthcare Charity, and with infrastructure support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC), Imperial Clinical Research Facility, and Clinical Research Network. S.M. is currently supported by a Future Leaders Mentorship Award from the European Association for the Study of Diabetes. A.J. was a Diabetes UK George Alberti Clinical Research Fellow when contributing to this study. S.E. received a Senior Investigator Award from Wellcome Trust. A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science. Part of this work was funded in Oxford by the Wellcome Trust (grants 095101 and 200837 [both to A.L.G.]). The research was also funded by the NIHR Oxford and BRC (to A.L.G.).Accepted version, submitted versio

Sulfur analysis of Bolu-Mengen lignite before and after microbiological treatment using reductive pyrolysis and gas chromatography/mass spectrometry

Atmospheric pressure-temperature programmed reduction coupled with on-line mass spectrometry (AP-TPR/MS) is used for the first time on microbiologically treated coal samples as a technique to monitor the degree of desulfurization of the various sulfur functionalities. The experimental procedure enables the identification of both organic and inorganic sulfur species present in the coal matrix. A better insight in the degradation of the coal matrix and the accompanying processes during the AP-TPR experiment is obtained by a quantitative differentiation of the sulfur. The determination of the sulfur balance for the reductive pyrolysis gives an overview of the side reactions and their relative contribution in the total process. The volatile sulfur species are unambiguously identified using AP-TPR off-line coupled with gas chromatography/mass spectrometry (GC/MS). In this way, fundamental mechanisms and reactions that occur during the reductive pyrolysis could be quantified, explaining the differences in AP-TPR recoveries. Therefore, this study gives a clearer view on the possibilities and limitations of AP-TPR as a technique to monitor sulfur functionalities in coal

Fenestrated-branched endovascular repair for distal thoracoabdominal aortic pathology after total aortic arch replacement with frozen elephant trunk

Objective: To report the outcomes of fenestrated-branched endovascular repair (FBEVAR) for thoracoabdominal aortic pathology after total aortic arch replacement with frozen elephant trunk (TAR+FET). Methods: Interrogation of prospectively maintained databases from four high-volume aortic centers identified consecutive patients treated with distal FBEVAR after prior TAR+FET between August 2013 and September 2020. The primary end point was 30-day/in-hospital mortality. Secondary end points were technical success, early clinical success, midterm survival, and freedom from reintervention. Data are presented as median (interquartile range). Results: A total of 39 patients (21 men; median age, 73 years [67-75 years]) with degenerative (n = 22) and postdissection thoracoabdominal aortic aneurysms (n = 17) (median diameter, 71 mm [61-78 mm]) were identified. Distal FBEVAR was intended in 27 patients (median interval, 9.8 months [6.2-16.6 months]), anticipated in 7, and unexpected in 5. A total of 31 patients had a two- (n = 24) or three-stage (n = 7) distal FBEVAR. Renovisceral target vessel preservation was 99.3% (145 of 146). Early primary and secondary technical success was 92% and 97%, respectively. Thirty-day mortality was 2.6% (n = 1; respiratory failure and spinal cord ischemia [SCI]). Six survivors also developed SCI, which was associated with complete (n = 4) or partial recovery (n = 2) at hospital discharge. No patients required renal replacement therapy or suffered a stroke. Early clinical success was 95%. Median follow-up was 30.5 months (23.7-49.7 months). Eleven patients required 16 late reinterventions. Estimated 3-year survival and freedom from reintervention were 84% ± 6% and 63% ± 10%, respectively. Conclusions: Distal FBEVAR after prior TAR+FET is associated with high technical success and low early mortality. The risk of SCI is significant although the majority of patients demonstrate full or partial recovery before hospital discharge. Midterm patient survival is favorable, but there remains a high requirement for late reintervention. FBEVAR represents an acceptable alternative to distal open thoracoabdominal aortic aneurysm repair

Fucosylated AGP glycopeptides as biomarkers of HNF1A-Maturity onset diabetes of the young

Aims: We previously demonstrated that antennary fucosylated N-glycans on plasma proteins are regulated by HNF1A and can identify cases of Maturity-Onset Diabetes of the Young caused by HNF1A variants (HNF1A-MODY). Based on literature data, we further postulated that N-glycans with best diagnostic value mostly originate from alpha-1-acid glycoprotein (AGP). In this study we analyzed fucosylation of AGP in subjects with HNF1A-MODY and other types of diabetes aiming to evaluate its diagnostic potential. Methods: A recently developed LC-MS method for AGP N-glycopeptide analysis was utilized in two independent cohorts: a) 466 subjects with different diabetes subtypes to test the fucosylation differences, b) 98 selected individuals to test the discriminative potential for pathogenic HNF1A variants. Results: Our results showed significant reduction in AGP fucosylation associated to HNF1A-MODY when compared to other diabetes subtypes. Additionally, ROC curve analysis confirmed significant discriminatory potential of individual fucosylated AGP glycopeptides, where the best performing glycopeptide had an AUC of 0.94 (95% CI 0.90–0.99). Conclusions: A glycopeptide based diagnostic tool would be beneficial for patient stratification by providing information about the functionality of HNF1A. It could assist the interpretation of DNA sequencing results and be a useful addition to the differential diagnostic process.publishedVersio

Ursodeoxycholic acid to reduce adverse perinatal outcomes for intrahepatic cholestasis of pregnancy: the PITCHES RCT

Background: Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and raised serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment, but without an adequate evidence base. / Objective: We aimed to evaluate whether or not ursodeoxycholic acid reduces adverse perinatal outcomes in affected women. / Design: Multicentre, masked, randomised, placebo-controlled, two-arm, parallel-group trial. / Setting: Thirty-three UK maternity units. / Participants: Women with intrahepatic cholestasis of pregnancy aged ≥ 18 years, between 20+0 and 40+6 weeks’ gestation with a singleton or twin pregnancy and no known lethal fetal anomaly. / Interventions: Women were randomly assigned (1 : 1 allocation ratio) to take ursodeoxycholic acid tablets or matched placebo tablets, at an equivalent dose of 1000 mg daily, titrated as needed. / Main outcome measures: The primary outcome was a composite of perinatal death (in utero fetal death after randomisation or known neonatal death up to 7 days) or preterm delivery (< 37 weeks’ gestation) or neonatal unit admission for at least 4 hours (from birth until hospital discharge). Each infant was counted once within this composite. Analyses were by intention to treat. / Results: Between 23 December 2015 and 7 August 2018, 605 women were randomised, with 305 women allocated to the ursodeoxycholic acid arm and 300 women to the placebo arm. There was no evidence of a significant difference in the incidence of the primary outcome between the groups: 23.0% (74 out of 322 infants) in the ursodeoxycholic acid group compared with 26.7% (85 out of 318 infants) in the placebo group; adjusted risk ratio 0.85 (95% confidence interval 0.62 to 1.15). There was no evidence of a significant difference in total costs (maternal, infant and the cost of ursodeoxycholic acid) between the two trial groups. There were two serious adverse events in the ursodeoxycholic acid group and six in the placebo group. / Limitations: Limitations include a primary outcome event rate in the control group that was lower than that estimated for the sample size calculation, but the lack of evidence of effect in all analyses suggests that it is unlikely that the trial had insufficient power. / Conclusions: In this clinical trial of ursodeoxycholic acid in women with intrahepatic cholestasis of pregnancy, there is no evidence that it is effective in reducing a composite of adverse perinatal outcomes. / Future work: Future research should aim to elucidate the aetiology and pathophysiology of adverse perinatal outcomes, particularly stillbirth, in women with intrahepatic cholestasis of pregnancy to assist the development of an effective preventative treatment. Further exploratory analyses may identify groups of women who might respond to ursodeoxycholic acid treatment. / Trial registration: Current Controlled Trials ISRCTN91918806. / Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 9. See the NIHR Journals Library website for further project information

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)