Competitive formation of spiro and ansa derivatives in the reactions of tetrafluorobutane-1,4-diol with hexachlorocyclotriphosphazene: a comparison with butane-1,4-diol

Reaction of hexachlorocyclotriphosphazene, N3P3Cl6 (1), in two stoichiometries (1:1.2 and 1:3) with the sodium derivative of the fluorinated diol, 2,2,3,3-tetrafluorobutane-1,4-diol, (2), in THF solution at room temperature afforded six products, whose structures have been characterized by X-ray crystallography and 1H, 19F and 31P NMR spectroscopy: the mono-spiro compound, N3P3Cl4(OCH2CF2CF2CH2O), (3), its ansa isomer, (4), a di-spiro derivative N3P3Cl2(OCH2CF2CF2CH2O)2, (5), its spiro-ansa (6) and non-gem cis bis-ansa (7) isomers and a tri-spiro compound N3P3(OCH2CF2CF2CH2O)3, (8). The tri-spiro derivative (8) was also formed in the reaction of the ansa compound (4) with diol (2) in a 1:3 ratio in THF at room temperature. The reactions of (1) with step-wise additions of (2) were also investigated at low temperature (-780C) to give the same range of products as at room temperature. The results of all reactions are compared with previous work on the reactions of (1) with butane-1,4-diol/pyridine mixtures and with the reaction of hexafluorocyclotriphosphazene, N3P3F6 (9), with the silyl derivative of the diol (2), (Me3SiOCH2CF2)2, in a 1:0.4 mole ratio in the same solvent, THF

Long-term surgical and patient-reported outcomes of Hirschsprung Disease

Background: Information is needed regarding the complex relationships between long-term functional outcomes and health-related quality of life (HRQoL) in Hirschsprung's Disease (HSCR). We describe longterm outcomes across multiple domains, completing a core outcome set through to adulthood. Methods: HSCR patients operated at a single center over a 35-year period (1978-2013) were studied. Patients completed detailed questionnaires on bowel and urologic function, and HRQOL. Patients with learning disability (LD) were excluded. Outcomes were compared to normative data. Data are reported as median [IQR] or mean (SD). Results: 186 patients (median age 28 [18-32] years; 135 males) completed surveys. Bowel function was reduced (BFS 17 [14-19] vs. 19 [19-20], p < 0.0001;eta(2) = 0.22). Prevalence and severity of fecal soiling and fecal awareness improved with age ( p < 0.05 for both). Urinary incontinence was more frequent than controls, most of all in 13-26y females (65% vs. 31%, p = 0.003). In adults, this correlated independently with constipation symptoms (OR 3.18 [1.4-7.5], p = 0.008). HRQoL outcomes strongly correlated with functional outcome: 42% of children demonstrated clinically significant reductions in overall PedsQL score, and poor bowel outcome was strongly associated with impaired QOL (B = 22.7 [12.7- 32.7], p < 0.001). In adults, GIQLI scores were more often impacted in patients with extended segment disease. SF-36 scores were reduced relative to population level data in most domains, with large effect sizes noted for females in General Health (g = 1.19) and Social Wellbeing (g = 0.8). Conclusion: Functional impairment is common after pull-through, but bowel function improves with age. Clustering of poor functional outcomes across multiple domains identifies a need for early recognition and long-term support for these patients. (C) 2021 Elsevier Inc. All rights reserved.Peer reviewe

An investigation of minimisation criteria

Minimisation can be used within treatment trials to ensure that prognostic factors are evenly distributed between treatment groups. The technique is relatively straightforward to apply but does require running tallies of patient recruitments to be made and some simple calculations to be performed prior to each allocation. As computing facilities have become more widely available, minimisation has become a more feasible option for many. Although the technique has increased in popularity, the mode of application is often poorly reported and the choice of input parameters not justified in any logical way

Remote ischaemic conditioning in necrotising enterocolitis: a phase I feasibility and safety study

OBJECTIVE: Remote ischaemic conditioning (RIC) improves the outcome of experimental necrotising enterocolitis (NEC) by preserving intestinal microcirculation. The feasibility and safety of RIC in preterm infants with NEC are unknown. The study aimed to assess the feasibility and safety of RIC in preterm infants with suspected or confirmed NEC. DESIGN: Phase I non-randomised pilot study conducted in three steps: step A to determine the safe duration of limb ischaemia (up to 4 min); step B to assess the safety of 4 repeated cycles of ischaemia-reperfusion at the maximum tolerated duration of ischaemia determined in step A; step C to assess the safety of applying 4 cycles of ischaemia-reperfusion on two consecutive days. SETTING: Level III neonatal intensive care unit, The Hospital for Sick Children (Toronto, Canada). PATIENTS: Fifteen preterm infants born between 22 and 33 weeks gestational age. INTERVENTION: Four cycles of ischaemia (varying duration) applied to the limb via a manual sphygmomanometer, followed by reperfusion (4 min) and rest (5 min), repeated on two consecutive days. OUTCOMES: The primary outcomes were (1) feasibility defined as RIC being performed as planned in the protocol, and (2) safety defined as perfusion returning to baseline within 4 min after cuff deflation. RESULTS: Four cycles/day of limb ischaemia (4 min) followed by reperfusion (4 min) and a 5 min gap, repeated on two consecutive days was feasible and safe in all neonates with suspected or confirmed NEC. CONCLUSIONS: This study is pivotal for designing a future randomised controlled trial to assess the efficacy of RIC in preterm infants with NEC

Integrated photonic building blocks for next-generation astronomical instrumentation I: the multimode waveguide

We report on the fabrication and characterization of composite multimode waveguide structures that consist of a stack of single-mode waveguides fabricated by ultrafast laser inscription. We explore 2 types of composite structures; those that consist of overlapping single-mode waveguides which offer the maximum effective index contrast and non overlapped structures which support multiple modes via strong evanescent coupling. We demonstrate that both types of waveguides have negligible propagation losses (to within experimental uncertainty) for light injected with focal ratios >8, which corresponds to the cutoff of the waveguides. We also show that right below cutoff, there is a narrow region where the injected focal ratio is preserved (to within experimental uncertainty) at the output. Finally, we outline the major application of these highly efficient waveguides; in a device that is used to reformat the light in the focal plane of a telescope to a slit, in order to feed a diffraction-limited spectrograph.Comment: 15 pages, 11 figures, accepted to Optics Expres

Evidence of the Generation of Isosaccharinic Acids and Their Subsequent Degradation by Local Microbial Consortia within Hyper-Alkaline Contaminated Soils, with Relevance to Intermediate Level Radioactive Waste Disposal

The contamination of surface environments with hydroxide rich wastes leads to the formation of high pH (>11.0) soil profiles. One such site is a legacy lime works at Harpur Hill, Derbyshire where soil profile indicated in-situ pH values up to pH 12. Soil and porewater profiles around the site indicated clear evidence of the presence of the α and β stereoisomers of isosaccharinic acid (ISA) resulting from the anoxic, alkaline degradation of cellulosic material. ISAs are of particular interest with regards to the disposal of cellulosic materials contained within the intermediate level waste (ILW) inventory of the United Kingdom, where they may influence radionuclide mobility via complexation events occurring within a geological disposal facility (GDF) concept. The mixing of uncontaminated soils with the alkaline leachate of the site resulted in ISA generation, where the rate of generation in-situ is likely to be dependent upon the prevailing temperature of the soil. Microbial consortia present in the uncontaminated soil were capable of surviving conditions imposed by the alkaline leachate and demonstrated the ability to utilise ISAs as a carbon source. Leachate-contaminated soil was sub-cultured in a cellulose degradation product driven microcosm operating at pH 11, the consortia present were capable of the degradation of ISAs and the generation of methane from the resultant H2/CO2 produced from fermentation processes. Following microbial community analysis, fermentation processes appear to be predominated by Clostridia from the genus Alkaliphilus sp, with methanogenesis being attributed to Methanobacterium and Methanomassiliicoccus sp. The study is the first to identify the generation of ISA within an anthropogenic environment and advocates the notion that microbial activity within an ILW-GDF is likely to influence the impact of ISAs upon radionuclide migration

International survey on the management of esophageal atresia

IntroductionBecause many aspects of the management of esophageal atresia (EA) are still controversial, we evaluated the practice patterns of this condition across Europe. MethodsA survey was completed by 178 delegates (from 45 [27 European] countries; 88% senior respondents) at the EUPSA-BAPS 2012. ResultsApproximately 66% of respondents work in centers where more than five EA repairs are performed per year. Preoperatively, 81% of respondents request an echocardiogram, and only 43% of respondents routinely perform preoperative bronchoscopy. Approximately 94% of respondents prefer an open approach, which is extrapleural in 71% of respondents. There were no differences in use of thoracoscopy between Europeans (10%) and non-Europeans (11%, p=nonsignificant). Approximately 60% of respondents measure the gap intraoperatively. A transanastomotic tube (90%) and chest drain (69%) are left in situ. Elective paralysis is adopted by 56% of respondents mainly for anastomosis tension (65%). About 72% of respondents routinely request a contrast study on postoperative day 7 (2-14). Approximately 54% of respondents use parenteral nutrition, 40% of respondents start transanastomotic feeds on postoperative day 1, and 89% of respondents start oral feeds after postoperative day 5. Pure EA: 46% of respondents work in centers that repair two or more than two pure EA a year. About 60% of respondents opt for delayed primary anastomosis at 3 months (1-12 months) with gastrostomy formation without esophagostomy. Anastomosis is achieved with open approach by 85% of respondents. About 47% of respondents attempt elongation of esophageal ends via Foker technique (43%) or with serial dilations with bougies (41%). Approximately 67% of respondents always attempt an anastomosis. Gastric interposition is the commonest esophageal substitution. ConclusionMany aspects of EA management are lacking consensus. Minimally invasive repair is still sporadic. We recommend establishment of an EA registry

Protein aggregation and calcium dysregulation are hallmarks of familial Parkinson's disease in midbrain dopaminergic neurons

Mutations in the SNCA gene cause autosomal dominant Parkinson’s disease (PD), with loss of dopaminergic neurons in the substantia nigra, and aggregation of α-synuclein. The sequence of molecular events that proceed from an SNCA mutation during development, to end-stage pathology is unknown. Utilising human-induced pluripotent stem cells (hiPSCs), we resolved the temporal sequence of SNCA-induced pathophysiological events in order to discover early, and likely causative, events. Our small molecule-based protocol generates highly enriched midbrain dopaminergic (mDA) neurons: molecular identity was confirmed using single-cell RNA sequencing and proteomics, and functional identity was established through dopamine synthesis, and measures of electrophysiological activity. At the earliest stage of differentiation, prior to maturation to mDA neurons, we demonstrate the formation of small β-sheet-rich oligomeric aggregates, in SNCA-mutant cultures. Aggregation persists and progresses, ultimately resulting in the accumulation of phosphorylated α-synuclein aggregates. Impaired intracellular calcium signalling, increased basal calcium, and impairments in mitochondrial calcium handling occurred early at day 34–41 post differentiation. Once midbrain identity fully developed, at day 48–62 post differentiation, SNCA-mutant neurons exhibited mitochondrial dysfunction, oxidative stress, lysosomal swelling and increased autophagy. Ultimately these multiple cellular stresses lead to abnormal excitability, altered neuronal activity, and cell death. Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease

Metabolizable Energy Content of Breastmilk Supports Normal Growth in Exclusively Breastfed Icelandic Infants to Age 6 Months

Funding Information: This research was funded by the Icelandic Research Fund ( 196157-053 ) and the University of Iceland Research Fund (to Inga Thorsdottir). All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the National Institute for Health and Care Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Publisher Copyright: © 2023 The AuthorsBackground: Neither the global population nor individual countries have reached the World Health Organization (WHO) target of ≥50% of infants exclusively breastfed (EBF) until 6 mo. This may partly be because of the perceptions of insufficient milk and energy supply to meet rapid growth and development needs. Objectives: In a longitudinal observational study, we aimed to determine whether breastmilk energy content is sufficient to support growth during EBF until 6 mo. Methods: A sample of 27 EBF infants was dosed with doubly labeled water (DLW) at 5.6 mo to measure body composition, breastmilk intake, energy intake, and the metabolizable energy (ME) content of their mother's breastmilk over the following week. Z-scores were calculated for anthropometry using WHO reference data and for fat-free mass (FFM) and fat mass (FM) using United Kingdom reference data. Results: Anthropometric z-scores from birth indicated normal weight and length growth patterns. At ∼6 mo, the mean ± standard deviation (SD) FFM z-score was 0.22 ± 1.07, and the FM z-score was 0.78 ± 0.70, significantly >0. In the 22 infants with acceptable data, the mean ± SD measured intake of breastmilk was 983 ± 170 g/d and of energy, 318 ± 60 kJ/kg/d, equivalent to 75.9 ± 14.3 kcal/kg/d. The mean ME content of breastmilk was 2.61 kJ/g [standard error (SE) 0.1], equivalent to 0.62 kcal/g (SE 0.02). Mothers were positive toward breastfeeding, on paid maternity leave (planned mean 10 mo), and many (56%) had received specialized breastfeeding support. Conclusions: The evidence from this study confirms that when mothers are motivated and supported without economic restraints, breastmilk intake and the energy supplied by breastmilk to EBF infants at 6 mo of age is sufficient to support normal growth patterns. There was no evidence of constraint on FFM, and other studies show that high FM in EBF infants is likely to be transient. These data further support the recommendation for EBF ≤6 mo of age for body composition. This trial was registered at clinicaltrials.gov as NCT02586571.Peer reviewe

mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria

The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using ( S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG). Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. To assess hepatic glutathione dysregulation and liver disease, we present [18F]FSPG PET as a noninvasive diagnostic tool to monitor therapeutic response in argininosuccinic aciduria. Human hASL mRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASL mRNA therapy corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis. These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria. </p