Synthetic studies towards virantmycin.

The use of vinylphosphonium salts in the construction of acyclic and cyclic systems by both ourselves and others is reviewed.The alkylthio and arylthio vinylphosphonium salts are used in an unsuccessful approach to the synthesis of the tetrahydroquinoline natural product virantmycin.The use of this approach in the early stages of a synthesis of carbaprostacyclin and analogues is also examined.The synthesis of virantmycin was also investigated using a regioselective Dieckmann reaction. Two procedures have been developed for the synthesis of the mixed 0,S-diester required to study the cyclisation. The first of these has as the key step a one carbon homologation reaction of a benzaldehyde to a phenylacetic acid derivative. The second relies on a pericyclic rearrangement reaction. The latter route has proved more successful and the Dieckmann product has been made using this procedure. Applications of this to the synthesis of virantmycin are discussed.The use of methyl methylsulphinylmethyl sulphide in the one carbon homologation for the synthesis of the Dieckmann precursor has been extended. Thus a set of conditions has been developed for the synthesis of chloroketenedithioacetals from ketenedithioacetal S-oxides which complements the only other known set of conditions for this transformation. Under our conditions the ketene dithioacetal S-oxide derived from 2-aminobenzaldehyde cyclises to give two indoles. A modified set of conditions are presented which give rise to anomalous products. In the light of this a mechanism is proposed.Finally the use of this strategy is extended to a synthesis of benzofurans and further discussion shows how this might be used in a general preparation of thiol esters and in the synthesis of other heterocyclic systems or natural products

Development and initial psychometric properties of the Warwick–Edinburgh Mental Wellbeing Scale-Intellectual Disability version

Background: The Warwick–Edinburgh Mental Wellbeing Scale (WEMWBS; Tennant et al., 2007) is yet to be validated in the intellectual disability (ID) population. The aim of this study was to report the development process and assess the psychometric properties of a newly adapted version of the WEMWBS and the Short WEMWBS for individuals with mild to moderate IDs (WEMWBS-ID/SWEMWBS-ID). / Method: The WEMWBS item wordings and response options were revised by clinicians and researchers expert in the field of ID, and a visual aid was added to the scale. The adapted version was reviewed by 10 individuals with IDs. The measure was administered by researchers online using screenshare, to individuals aged 16+ years with mild to moderate IDs. Data from three UK samples were collated to evaluate the WEMWBS-ID (n = 96). A subsample (n = 22) completed the measure again 1 to 2 weeks later to assess test–retest reliability, and 95 participants additionally completed an adapted version of the adapted Rosenberg Self-Esteem Scale to examine convergent validity. Additional data from a Canadian sample (n = 27) were used to evaluate the SWEMWBS-ID (n = 123). / Results: The WEMWBS-ID demonstrated good internal consistency (ω = 0.77–0.87), excellent test–retest reliability [intraclass correlation coefficient (ICC) =.88] and good convergent validity with the self-esteem scale (r =.48–.60) across samples. A confirmatory factor analysis for a single factor model demonstrated an adequate fit. The SWEMWBS-ID showed poor to good internal consistency (ω = 0.36–0.74), moderate test–retest reliability (ICC =.67) and good convergent validity (r =.48–.60) across samples, and a confirmatory factor analysis indicated good model fit for a single factor structure. / Conclusions: The WEMWBS-ID and short version demonstrated promising psychometric properties, when administered virtually by a researcher. Further exploration of the scales with larger, representative samples is warranted

Maternal valacyclovir and infant cytomegalovirus acquisition: a randomized controlled trial among HIV-infected women.

Background Studies in HIV-1-infected infants and HIV-1-exposed, uninfected infants link early cytomegalovirus (CMV) acquisition with growth delay and cognitive impairment. We investigated maternal valacyclovir to delay infant acquisition of CMV. Methods Pregnant women with HIV-1, HSV-2 and CD4 count >250 cells/µl were randomized at 34 weeks gestation to 500 mg twice-daily valacyclovir or placebo for 12 months. Maternal CMV DNA was measured in plasma at 34 weeks gestation, in cervical secretions at 34 and 38 weeks gestation, and in breast milk at 7 postpartum timepoints; infant CMV DNA was measured in dried blood spots at 8 timepoints including birth. Results Among 148 women, 141 infants were compared in intent-to-treat analyses. Maternal and infant characteristics were similar between study arms. Infant CMV acquisition did not differ between study arms, with 46/70 infants (66%) in placebo arm and 47/71 infants (66%) in the valacyclovir arm acquiring CMV; median time to CMV detection did not differ. CMV DNA was detected in 92% of 542 breast milk specimens with no difference in CMV level between study arms. Change in cervical shedding of CMV DNA between baseline and 38 weeks was 0.40-log greater in the placebo arm than the valacyclovir arm (p = 0.05). Conclusions In this cohort of HIV-1-seropositive mothers, two-thirds of infants acquired CMV by one year. Maternal valacyclovir had no effect on timing of infant CMV acquisition or breast milk CMV viral loads, although it modestly reduced cervical CMV shedding. Maternal prophylaxis to reduce infant CMV acquisition warrants further evaluation in trials with antiviral agents

Searching for Saturn's Dust Swarm: Limits on the size distribution of Irregular Satellites from km to micron sizes

We describe a search for dust created in collisions between the Saturnian irregular satellites using archival \emph{Spitzer} MIPS observations. Although we detected a degree scale Saturn-centric excess that might be attributed to an irregular satellite dust cloud, we attribute it to the far-field wings of the PSF due to nearby Saturn. The Spitzer PSF is poorly characterised at such radial distances, and we expect PSF characterisation to be the main issue for future observations that aim to detect such dust. The observations place an upper limit on the level of dust in the outer reaches of the Saturnian system, and constrain how the size distribution extrapolates from the smallest known (few km) size irregulars down to micron-size dust. Because the size distribution is indicative of the strength properties of irregulars, we show how our derived upper limit implies irregular satellite strengths more akin to comets than asteroids. This conclusion is consistent with their presumed capture from the outer regions of the Solar System.Comment: accepted to MNRA

Gallbladder Cancer Incidence Among American Indians and Alaska Natives, US, 1999–2004

BACKGROUND. Gallbladder cancer (GBC) is rare; however, it disproportionately affects the American Indian and Alaska Natives (AI/AN) population. The purpose of the study was to characterize GBC among AI/AN in the US population. METHODS. Cases of GBC diagnosed between 1999 and 2004 and collected by state-based cancer registries were included. Registry records were linked with Indian Health Service (IHS) administration records to decrease race misclassification of AI/AN. GBC rates and/or percent distributions for AI/AN and non-Hispanic whites (NHW) were calculated by sex, IHS region, age, and stage for all US counties and IHS Contract Health Service Delivery Area (CHSDA) counties, in which approximately 56% of US AI/AN individuals reside. RESULTS. In CHSDA counties, the GBC incidence rate among AI/AN was 3.3 per 100,000, which was significantly higher than that among NHW (P \u3c .05). Rates varied widely among IHS regions and ranged from 1.5 in the East to 5.5 in Alaska. Rates were higher among AI/AN females than males in all regions, except the Northern Plains. Higher percentages of GBC were diagnosed among AI/AN aged CONCLUSIONS. To the authors’ knowledge to date, this is the most comprehensive study of GBC incidence among AI/AN in the US. The accurate characterization of GBC in this population could help inform the development of interventions aimed at reducing morbidity and mortality from this diseas

Comparing Papanicolau smear, visual inspection with acetic acid and human papillomavirus cervical cancer screening methods among HIV-positive women by immune status and antiretroviral therapy

Background: A rigorous comparison of cervical cancer screening methods utilizing data on immune status, antiretroviral therapy (ART) and colposcopy-directed biopsy has not been performed among HIV-positive women. Methods: Between June and November 2009, 500 HIV-positive women were enrolled at an HIV treatment clinic in Nairobi, Kenya, and underwent Papanicolau (Pap) smear, visual inspection with acetic acid (VIA), human papillomavirus (HPV) and colposcopydirected biopsy (gold standard). Positive Pap smear (ASCUS, LSIL, HSIL), VIA, HPV and their combinations were compared with CIN2/3+. Sensitivity, specificity and AUC (sensitivity and 1-specificity) were compared using pairwise tests and multivariate logistic regression models that included age, CD4+ cell count and ART duration. Results:Of 500 enrolled, 498 samples were collected. On histology, there were 172 (35%) normal, 186 (37%) CIN1, 66 (13%) CIN2, 47 (9%) CIN3 and 27 (5%) indeterminate. Pap (ASCUS+) was the most sensitive screening method (92.7%), combination of both Pap (HSIL+) and VIA positive was the most specific (99.1%) and Pap (HSIL+) had the highest AUC (0.85). In multivariate analyses, CD4+ cell count of 350 cells/ml or less was associated with decreased HPV specificity (P=0.002); ART duration of less than 2 years was associated with decreased HPV (P=0.01) and VIA (P=0.03) specificity; and age less than 40 years was associated with increased VIA sensitivity (P Conclusion: Pap smear is a robust test among HIV-positive women regardless of immune status or ART duration. Results should be cautiously interpreted when using HPV among those younger, immunosuppressed or on ART less than 2 years, and when using VIA among those aged 40 years or more

A minimal binding footprint on CD1d-glycolipid is a basis for selection of the unique human NKT TCR

Although it has been established how CD1 binds a variety of lipid antigens (Ag), data are only now emerging that show how αβ T cell receptors (TCRs) interact with CD1-Ag. Using the structure of the human semiinvariant NKT TCR–CD1d–α-galactosylceramide (α-GalCer) complex as a guide, we undertook an alanine scanning mutagenesis approach to define the energetic basis of this interaction between the NKT TCR and CD1d. Moreover, we explored how analogues of α-GalCer affected this interaction. The data revealed that an identical energetic footprint underpinned the human and mouse NKT TCR–CD1d–α-GalCer cross-reactivity. Some, but not all, of the contact residues within the Jα18-encoded invariant CDR3α loop and Vβ11-encoded CDR2β loop were critical for recognizing CD1d. The residues within the Vα24-encoded CDR1α and CDR3α loops that contacted the glycolipid Ag played a smaller energetic role compared with the NKT TCR residues that contacted CD1d. Collectively, our data reveal that the region distant to the protruding Ag and directly above the F′ pocket of CD1d was the principal factor in the interaction with the NKT TCR. Accordingly, although the structural footprint at the NKT TCR–CD1d–α-GalCer is small, the energetic footprint is smaller still, and reveals the minimal requirements for CD1d restriction

Pharmacists in Pharmacovigilance: Can Increased Diagnostic Opportunity in Community Settings Translate to Better Vigilance?

The pharmacy profession has undergone substantial change over the last two to three decades. Whilst medicine supply still remains a central function, pharmacist’s roles and responsibilities have become more clinic and patient focused. In the community (primary care), pharmacists have become important providers of healthcare as Western healthcare policy advocates patient self-care. This has resulted in pharmacists taking on greater responsibility in managing minor illness and the delivery of public health interventions. These roles require pharmacists to more fully use their clinical skills, and often involve diagnosis and therapeutic management. Community pharmacists are now, more than ever before, in a position to identify, record and report medication safety incidents. However, current research suggests that diagnostic ability of community pharmacists is questionable and they infrequently report to local or national schemes. The aim of this paper is to highlight current practice and suggest ways in which community pharmacy can more fully contribute to patient safety

The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.

Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma

Multi-domain clinical natural language processing with MedCAT: The Medical Concept Annotation Toolkit

Electronic health records (EHR) contain large volumes of unstructured text, requiring the application of information extraction (IE) technologies to enable clinical analysis. We present the open source Medical Concept Annotation Toolkit (MedCAT) that provides: (a) a novel self-supervised machine learning algorithm for extracting concepts using any concept vocabulary including UMLS/SNOMED-CT; (b) a feature-rich annotation interface for customizing and training IE models; and (c) integrations to the broader CogStack ecosystem for vendor-agnostic health system deployment. We show improved performance in extracting UMLS concepts from open datasets (F1:0.448-0.738 vs 0.429-0.650). Further real-world validation demonstrates SNOMED-CT extraction at 3 large London hospitals with self-supervised training over ∼8.8B words from ∼17M clinical records and further fine-tuning with ∼6K clinician annotated examples. We show strong transferability (F1 > 0.94) between hospitals, datasets and concept types indicating cross-domain EHR-agnostic utility for accelerated clinical and research use cases