The Effective Fragment Molecular Orbital Method for Fragments Connected by Covalent Bonds

We extend the effective fragment molecular orbital method (EFMO) into treating fragments connected by covalent bonds. The accuracy of EFMO is compared to FMO and conventional ab initio electronic structure methods for polypeptides including proteins. Errors in energy for RHF and MP2 are within 2 kcal/mol for neutral polypeptides and 6 kcal/mol for charged polypeptides similar to FMO but obtained two to five times faster. For proteins, the errors are also within a few kcal/mol of the FMO results. We developed both the RHF and MP2 gradient for EFMO. Compared to ab initio, the EFMO optimized structures had an RMSD of 0.40 and 0.44 {\AA} for RHF and MP2, respectively.Comment: Revised manuscrip

Experiences of parenting and clinical intervention for mothers affected by personality disorder: a pilot qualitative study combining parent and clinician perspectives

Background: Evidence-based parenting programmes are recommended for the treatment of child mental health difficulties. Families with complex psychosocial needs show poorer retention and outcomes when participating in standard parenting programmes. The Helping Families Programme (HFP) is a 16-week community-based parenting intervention designed to meet the needs of these families, including families with parental personality disorder. This study aimed to explore the help seeking and participatory experiences of parents with a diagnosis of personality disorder. It further aimed to examine the acceptability of referral and intervention processes for the HFP from the perspectives of (i) clinicians referring into the programme; and (ii) referred parents. Method: Semi-structured interviews were conducted with parents recruited to receive HFP (n = 5) as part of a research case series and the referring NHS child and adolescent mental health service (CAMHS) clinicians (n = 5). Transcripts were analysed using Interpretive Phenomenological Analysis. Results: Four themes were identified for parents: (i) the experience of parenthood, (ii) being a parent affected by personality disorder, (iii) experience of the intervention, and (iv) qualities of helping. Three themes emerged for clinicians: (i) challenges of addressing parental need, (ii) experience of engaging parents with personality disorders and (iii) limited involvement during HFP. Comparison of parent and clinician themes led to the identification of two key interlinked themes: (i) concerns prior to receiving the intervention, and (ii) the challenges of working together without a mutual understanding. Conclusions: This pilot study identifies potentially significant challenges of working with parents affected by personality disorder and engaging them in HFP and other similar interventions. Results have important wider clinical implications by highlighting potential barriers to engagement and participation and providing insights on how these barriers might be overcome. Findings have been used to inform the referral and intervention processes of a pilot RCT and further intervention development

The endogenous caspase-8 inhibitor c-FLIPL regulates ER morphology and crosstalk with mitochondria

Components of the death receptors-mediated pathways like caspase-8 have been identified in complexes at intracellular membranes to spatially restrict the processing of local targets. In this study, we report that the long isoform of the cellular FLICE-inhibitory protein (c-FLIPL), a well- known inhibitor of the extrinsic cell death initiator caspase-8, localizes at the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs). ER morphology was disrupted and ER Ca2+-release as well as ER-mitochondria tethering were decreased in c-FLIP-/- mouse embryonic fibroblasts (MEFs). Mechanistically, c-FLIP ablation resulted in enhanced basal caspase-8 activation and in caspase-mediated processing of the ER-shaping protein reticulon-4 (RTN4) that was corrected by re-introduction of c-FLIPL and caspase inhibition, resulting in the recovery of a normal ER morphology and ER-mitochondria juxtaposition. Thus, the caspase-8 inhibitor c-FLIPL emerges as a component of the MAMs signaling platforms, where caspases appear to regulate ER morphology and ER-mitochondria crosstalk by impinging on ER-shaping proteins like the RTN4

Results from a blind and a non-blind randomised trial run in parallel: experience from the Estonian Postmenopausal Hormone Therapy (EPHT) Trial

<p>Abstract</p> <p>Background</p> <p>The Estonian Postmenopausal Hormone Therapy (EPHT) Trial assigned 4170 potential participants prior to recruitment to blind or non-blind hormone therapy (HT), with placebo or non-treatment the respective alternatives. Before having to decide on participation, women were told whether they had been randomised to the blind or non-blind trial. Eligible women who were still willing to join the trial were recruited. After recruitment participants in the non-blind trial (N = 1001) received open-label HT or no treatment, participants in the blind trial (N = 777) remained blinded until the end of the trial. The aim of this paper is to analyse the effect of blinding on internal and external validity of trial outcomes.</p> <p>Methods</p> <p>Effect of blinding was calculated as the hazard ratio of selected chronic diseases, total mortality and all outcomes. For analysing the effect of blinding on external validity, the hazard ratios from women recruited to the placebo arm and to the non-treatment arm were compared with those not recruited; for analysing the effect of blinding on internal validity, the hazard ratios from the blind trial were compared with those from the non-blind trial.</p> <p>Results</p> <p>The women recruited to the placebo arm had less cerebrovascular disease events (HR 0.43; 95% CI: 0.26-0.71) and all outcomes combined (HR 0.76; 95% CI: 0.63-0.91) than those who were not recruited. Among women recruited or not recruited to the non-treatment arm, no differences were observed for any of the outcomes studied.</p> <p>Among women recruited to the trial, the risk for coronary heart disease events (HR 0.77; 95% CI: 0.64-0.93), cerebrovascular disease events (HR 0.66; 95%CI: 0.47-0.92), and all outcomes combined (HR 0.82; 95% CI: 0.72-0.94) was smaller among participants in the blind trial than in the non-blind trial. There was no difference between the blind and the non-blind trial for total cancer (HR 0.95; 95% CI: 0.64-1.42), bone fractures (0.93; 95% CI: 0.74-1.16), and total mortality (HR 1.03; 95% CI: 0.53-1.98).</p> <p>Conclusions</p> <p>The results from blind and non-blind trials may differ, even if the target population is the same. Blinding may influence both internal and external validity. The effect of blinding may vary for different outcome events.</p> <p>Trial registration</p> <p>[<a href="http://www.controlled-trials.com/ISRCTN35338757">ISRCTN35338757</a>]</p

Coating and Density Distribution Analysis of Commercial Ciprofloxacin Hydrochloride Monohydrate Tablets by Terahertz Pulsed Spectroscopy and Imaging

Terahertz pulsed spectroscopy was used to qualitatively detect ciprofloxacin hydrochloride monohydrate (CPFX·HCl·H2O) in tablets, and terahertz pulsed imaging (TPI) was used to scrutinize not only the coating state but also the density distribution of tablets produced by several manufacturers. TPI was also used to evaluate distinguishability among these tablets. The same waveform, which is a unique terahertz absorption spectrum derived from pure CPFX·HCl·H2O, was observed in all of the crushed tablets and in pure CPFX·HCl·H2O. TPI can provide information about the physical states of coated tablets. Information about the uniformity of parameters such as a coating thickness and density can be obtained. In this study, the authors investigated the coating thickness distributions of film-coated CPFX·HCl·H2O from four different manufacturers. Unique terahertz images of the density distributions in these commercial tablets were obtained. Moreover, B-scan (depth) images show the status of the coating layer in each tablet and the density map inside the tablets. These features would reflect differences resulting from different tablet-manufacturing processes

"Summary Page": a novel tool that reduces omitted data in research databases

<p>Abstract</p> <p>Background</p> <p>Data entry errors are common in clinical research databases. Omitted data are of particular concern because they are more common than erroneously inserted data and therefore could potentially affect research findings. However, few affordable strategies for their prevention are available.</p> <p>Methods</p> <p>We have conducted a prospective observational study of the effect of a novel tool called "<it>Summary Page</it>" on the frequency of correction of omitted data errors in a radiation oncology research database between July 2008 and March 2009. "<it>Summary Page</it>" was implemented as an optionally accessed screen in the database that visually integrates key fields in the record. We assessed the frequency of omitted data on the example of the <it>Date of Relapse </it>field. We considered the data in this field to be omitted for all records that had empty <it>Date of Relapse </it>field and evidence of relapse elsewhere in the record.</p> <p>Results</p> <p>A total of 1,156 records were updated and 200 new records were entered in the database over the study period. "<it>Summary Page</it>" was accessed for 44% of all updated records and for 69% of newly entered records. Frequency of correction of the omitted date of cancer relapse was six-fold higher in records for which "<it>Summary Page</it>" was accessed (p = 0.0003).</p> <p>Conclusions</p> <p>"<it>Summary Page</it>" was strongly associated with an increased frequency of correction of omitted data errors. Further, controlled, studies are needed to confirm this finding and elucidate its mechanism of action.</p

Drug transport in brain via the cerebrospinal fluid

The human brain has no lymphatic system, but produces over a half-liter each day of cerebrospinal fluid. The cerebrospinal fluid is secreted at the choroid plexus and occupies the cavities of the four ventricles, as well as the cranial and spinal sub-arachnoid space. The cerebrospinal fluid moves over the surfaces of the brain and spinal cord and is rapidly absorbed into the general circulation. The choroid plexus forms the blood-cerebrospinal fluid barrier, and this barrier is functionally distinct from the brain microvascular endothelium, which forms the blood-brain barrier. Virtually all non-cellular substances in blood distribute into cerebrospinal fluid, and drug entry into cerebrospinal fluid is not an index of drug transport across the blood-brain barrier. Drug injected into the cerebrospinal fluid rapidly moves into the blood via bulk flow, but penetrates into brain tissue poorly owing to the limitations of diffusion. Drug transport into cerebrospinal fluid vs. brain interstitial fluid requires knowledge of the relative expression of transporters at the choroid plexus versus the brain microvascular endothelium

Three phylogenetic groups have driven the recent population expansion of Cryptococcus neoformans.

Cryptococcus neoformans (C. neoformans var. grubii) is an environmentally acquired pathogen causing 181,000 HIV-associated deaths each year. We sequenced 699 isolates, primarily C. neoformans from HIV-infected patients, from 5 countries in Asia and Africa. The phylogeny of C. neoformans reveals a recent exponential population expansion, consistent with the increase in the number of susceptible hosts. In our study population, this expansion has been driven by three sub-clades of the C. neoformans VNIa lineage; VNIa-4, VNIa-5 and VNIa-93. These three sub-clades account for 91% of clinical isolates sequenced in our study. Combining the genome data with clinical information, we find that the VNIa-93 sub-clade, the most common sub-clade in Uganda and Malawi, was associated with better outcomes than VNIa-4 and VNIa-5, which predominate in Southeast Asia. This study lays the foundation for further work investigating the dominance of VNIa-4, VNIa-5 and VNIa-93 and the association between lineage and clinical phenotype

Diagnostic and cost utility of whole exome sequencing in peripheral neuropathy.

OBJECTIVE: To explore the diagnostic utility and cost effectiveness of whole exome sequencing (WES) in a cohort of individuals with peripheral neuropathy. METHODS: Singleton WES was performed in individuals recruited though one pediatric and one adult tertiary center between February 2014 and December 2015. Initial analysis was restricted to a virtual panel of 55 genes associated with peripheral neuropathies. Patients with uninformative results underwent expanded analysis of the WES data. Data on the cost of prior investigations and assessments performed for diagnostic purposes in each patient was collected. RESULTS: Fifty patients with a peripheral neuropathy were recruited (median age 18 years; range 2-68 years). The median time from initial presentation to study enrollment was 6 years 9 months (range 2 months-62 years), and the average cost of prior investigations and assessments for diagnostic purposes AU$4013 per patient. Eleven individuals received a diagnosis from the virtual panel. Eight individuals received a diagnosis following expanded analysis of the WES data, increasing the overall diagnostic yield to 38%. Two additional individuals were diagnosed with pathogenic copy number variants through SNP microarray. CONCLUSIONS: This study provides evidence that WES has a high diagnostic utility and is cost effective in patients with a peripheral neuropathy. Expanded analysis of WES data significantly improves the diagnostic yield in patients in whom a diagnosis is not found on the initial targeted analysis. This is primarily due to diagnosis of conditions caused by newly discovered genes and the resolution of complex and atypical phenotypes