N-Alkylation and Aminohydroxylation of 2-Azidobenzenesulfonamide gives a Pyrrolobenzothiadiazepine precursor whereas attempted N-Alkylation of 2-Azidobenzamide gives Benzotriazinones and Quinazolinones

N-Alkylation of 2-azidobenzenesulfonamide with 5-bromopent-1-ene gave an N-pentenyl sulfonamide which underwent intramolecular aminohydroxylation to give an N-(2-azidoaryl)sulfonyl prolinol, a precursor for the synthesis of a pyrrolobenzothiadiazepine. The attempted N-alkylation of 2-azidobenzamide gave a separable mixture (~1:1) of a benzotriazinone and a quinazolinone in 72% combined yield. Other primary alkyl halides (3 examples) gave similar mixtures of benzotriazinones and quinazolinones. Benzylic, allylic, secondary and tertiary alkyl halides (5 examples) gave only the benzotriazinones in moderate yields. The results of mechanistic studies show the likely involvement of nitrene intermediates in the quinazolinone pathway and a second pathway involving a DMSO or dimethylsulfide mediated conversion of 2-azidobenzamide into the benzotriazinones

Type-specific oncogenic human papillomavirus infection in high grade cervical disease in New Zealand

BACKGROUND: The national Human Papillomavirus (HPV) Immunisation Programme in New Zealand was introduced in 2008, and involves routine vaccination of girls 12–13 years with a catch-up for females aged up to 19 years. The aims of this study were to measure the pre-vaccination prevalence of oncogenic HPV infection in women aged 20–69 years who were participating in the New Zealand National Cervical Screening Programme (NZ-NCSP) and who were: (1) referred with high grade cytology with a subsequent histologically-confirmed high grade cervical intraepithelial neoplasia (CIN2/3) or adenocarcinoma in situ (AIS); or (2) were in the wider group of women who had a cytological prediction of high grade squamous disease or glandular abnormality (ASC-H/ HSIL+/AGC/AIS). METHODS: Women aged 20–69 years appearing on the NZ-NCSP register between August 2009-February 2011 with a cytology record of ASC-H/HSIL+/AGC/AIS were invited to participate in the study. Liquid-based cytology specimens were tested for 37 HPV types using Linear Array genotyping. The prevalence of type-specific HPV infection was reported within women with histologically-confirmed CIN 2/3 and within the wider group with ASC-H/HSIL+/AGC/AIS cytology. Age-specific trends for the relative proportion of HPV 16/18 vs. other oncogenic types in CIN2/3 were assessed. RESULTS: A total of 594 women with ASC-H/HSIL+/AGC/AIS cytology and a valid HPV test were recruited; of these 356 (60%) had confirmed CIN2/3 and 6 (1%) had confirmed AIS or glandular dysplasia. Positivity rates for any oncogenic HPV infection and for HPV16 and/or 18 within confirmed CIN2/3-AIS were 95% (95%CI: 92-97%) and 60% (54-65%) respectively; in all women with ASC-H/HSIL+/AGC/AIS cytology it was 87% (84-89%) and 53% (49-57%), respectively. The most common reported HPV types in women with CIN 2/3 were 16 (51%), 52 (19%), 31 (17%), 33 (13%) and 18 (12%). A trend for higher rates of HPV 16/18 infection compared to other oncogenic types was observed in younger women (p=0.0006). CONCLUSIONS: The prevalence of HPV 16/18 in confirmed high grade disease in New Zealand is comparable to that observed in Australia and European countries. Test positivity rates for type 52 appear higher than in comparable studies in other developed countries. A greater proportion of high grade lesions in younger women appear to be associated with HPV 16/18 infection

A Hierachical Evolutionary Algorithm for Multiobjective Optimization in IMRT

Purpose: Current inverse planning methods for IMRT are limited because they are not designed to explore the trade-offs between the competing objectives between the tumor and normal tissues. Our goal was to develop an efficient multiobjective optimization algorithm that was flexible enough to handle any form of objective function and that resulted in a set of Pareto optimal plans. Methods: We developed a hierarchical evolutionary multiobjective algorithm designed to quickly generate a diverse Pareto optimal set of IMRT plans that meet all clinical constraints and reflect the trade-offs in the plans. The top level of the hierarchical algorithm is a multiobjective evolutionary algorithm (MOEA). The genes of the individuals generated in the MOEA are the parameters that define the penalty function minimized during an accelerated deterministic IMRT optimization that represents the bottom level of the hierarchy. The MOEA incorporates clinical criteria to restrict the search space through protocol objectives and then uses Pareto optimality among the fitness objectives to select individuals. Results: Acceleration techniques implemented on both levels of the hierarchical algorithm resulted in short, practical runtimes for optimizations. The MOEA improvements were evaluated for example prostate cases with one target and two OARs. The modified MOEA dominated 11.3% of plans using a standard genetic algorithm package. By implementing domination advantage and protocol objectives, small diverse populations of clinically acceptable plans that were only dominated 0.2% by the Pareto front could be generated in a fraction of an hour. Conclusions: Our MOEA produces a diverse Pareto optimal set of plans that meet all dosimetric protocol criteria in a feasible amount of time. It optimizes not only beamlet intensities but also objective function parameters on a patient-specific basis

The fishes of ascension Island, central Atlantic Ocean - new records and an annotated checklist

A checklist of the fishes of Ascension Island is presented. The species Rhincodon typus, Alopias superciliosus, Isurus oxyrinchus, Carcharhinus obscurus, Galeocerdo cuvier, Sphyrna lewini, Hexanchus griseus, Manta birostris, Gymnothorax vicinus, Hippocampus sp., Epinephelus itajara, Cookeolus japonicus, Apogon pseudomaculatus, Phaeoptyx pigmentaria, Remora albescens, Caranx bartholomaei, Carangoides ruber, Decapterus tabl, Seriola dumerili, Thalassoma sanctaehelenae, Cryptotomus sp., Ruvettus pretiosus, Acanthocybium solandri, Auxis rochei, Auxis thazard, Euthynnus alletteratus, Katsuwonus pelamis, Thunnus alalunga, Thunnus obesus, Xiphias gladius, Istiophorus platypterus, Kajikia albida, Makaira nigricans, Tetrapturus pfluegeri, Hyperoglyphe perciformis, Schedophilus sp., Cantherhines macrocerus, Sphoeroides pachygaster and Diodon eydouxii are recorded for the first time from Ascension Island. We have recognized two previous records as identification errors and indicate 11 other records as doubtful. Including the 40 new records, we now list 173 fish species from Ascension Island, of which 133 might be considered 'coastal fish species'. Eleven of these (8.3%) appear to be endemic to the island and a further 16 species (12%) appear to be shared endemics with St Helena Island.Darwin Initiative [EIDCF012]info:eu-repo/semantics/publishedVersio

Habitual physical activity (HPA) as a factor in sustained executive function in Alzheimer-type dementia: a cohort study

Evidence from studies on healthy older adults and mild cognitive impairment (MCI) populations suggests that physical activity interventions have a positive effect on executive function. In this study, we consider whether HPA is positively associated with executive function in Alzheimer's disease (AD). Eighty-two participants with a diagnosis of mild to moderate AD completed six measures of executive function. Objective measures of physical status were taken. In addition, informants completed questionnaires on the participants’ HPA and other lifestyle factors. A composite measure of executive function was the primary outcome. A multistage multiple regression was used to determine how much variance HPA accounted for. The final model comprised disease severity, cognitive reserve, cognitive activities, neuropsychiatric status and HPA status. The final model accounted for a total of 57% of the variance of executive performance, of which HPA itself accounted for 8% of the variance. HPA status is associated executive performance in an AD population even after controlling for key covariates. The findings encourage clinicians to recommend HPA and its cognitive benefits to AD patients and their carers

Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases.

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses

Prioritizing CD4 Count Monitoring in Response to ART in Resource-Constrained Settings: A Retrospective Application of Prediction-Based Classification

Luis Montaner and colleagues retrospectively apply a potential capacity-saving CD4 count prediction tool to a cohort of HIV patients on antiretroviral therapy