Experimental Realization of the Peregrine Soliton in Repulsive Two-Component Bose-Einstein Condensates.

We experimentally realize the Peregrine soliton in a highly particle-imbalanced two-component repulsive Bose-Einstein condensate in the immiscible regime. The effective focusing dynamics and resulting modulational instability of the minority component provide the opportunity to dynamically create a Peregrine soliton with the aid of an attractive potential well that seeds the initial dynamics. The Peregrine soliton formation is highly reproducible, and our experiments allow us to separately monitor the minority and majority components, and to compare with the single component dynamics in the absence or presence of the well with varying depths. We showcase the centrality of each of the ingredients leveraged herein. Numerical corroborations and a theoretical basis for our findings are provided through three-dimensional simulations emulating the experimental setting and via a one-dimensional analysis further exploring its evolution dynamics.

A polymorphism in the promoter of FRAS1 is a candidate SNP associated with metastatic prostate cancer.

BACKGROUND: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer). METHODS: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian. RESULTS: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years. CONCLUSIONS: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men.

A Signal Processing Approach to Pharmacokinetic Data Analysis.

The connection between pharmacokinetic models and system theory has been established for a long time. In this approach, the drug concentration is seen as the output of a system whose input is the drug administered at different times. In this article we further explore this connection. We show that system theory can be used to easily accommodate any therapeutic regime, no matter its complexity, allowing the identification of the pharmacokinetic parameters by means of a non-linear regression analysis. We illustrate how to exploit the properties of linear systems to identify non-linearities in the pharmacokinetic data. We also explore the use of bootstrapping as a way to compare populations of pharmacokinetic parameters and how to handle the common situation of using multiple hypothesis tests as a way to distinguish two different populations. Finally, we demonstrate how the bootstrap values can be used to estimate the distribution of derived parameters, as can be the allometric scale factors.

Efficacy of color lenses in abolishing photosensitivity: Beyond the one-type-fits-all approach?

OBJECTIVE: Red-light filtering lenses represent an additional option to medication in photosensitive epilepsy. Blue lenses (Clarlet Z1 F133) can dramatically reduce seizure frequency, with a substantial restriction in luminance that can limit their applicability in daily life. We investigated the efficacy of 4 blue lenses with higher transmittance and reduced chromatic distortion in abolishing the photoparoxysmal EEG response (PPR) compared to the gold-standard Z1 lenses. METHODS: We reviewed EEG data during photic-and pattern stimulation in 19 consecutive patients (6-39 years) with photosensitivity (PS). Stimulation was performed at baseline and while wearing Z1 and the four new lenses. Lenses were tested in the same session by asking the patient to wear them in a sequentially randomized fashion while stimulating again with the most provocative photic/pattern stimuli. The primary outcome was the change in the initial PPR observed for each lens, categorized as no change, reduction, and abolition. RESULTS: Photosensitivity was detected in 17 subjects (89.5%); pattern sensitivity (PtS) was identified in 14 patients (73.7%). The highest percentages of PPR abolition/reduction were observed with Z1, for both PS and PtS. Regarding the new lenses, B1 + G1 offered the best rates, followed by B1 + G2. B1 + G3 and B1 showed lower efficacy rates, particularly for PtS. In the comparative analysis, no significant differences in PPR suppression were detected between the five lenses for PS. For PtS, the capacity of Z1 for PPR abolition was significantly higher compared with B1 + G3 and B1. CONCLUSIONS: This preliminary study suggests efficacy of the new group of blue lenses with potentially greater tolerability, particularly in regions with fewer sunlight hours during winter. In line with the current trend for personalized approach to treatment, this study suggests that in some patients there might be scope in extending the testing to offer the lens with the higher transmittance effective in abolishing the PPR.

Experimental manipulation of beliefs about the importance of thoughts and the effect on an aggressive impulse.

BACKGROUND: Cognitive models of obsessive-compulsive disorder attribute a causal role to maladaptive beliefs. AIMS: To test this hypothesis, we manipulated Overimportance of Thoughts (OT) beliefs and experimentally evaluated their effect on the response to an induced aggressive impulse. METHOD: Eighty-five participants completed a battery of self-report instruments assessing obsession symptoms, thought control, affectivity and obsessive beliefs, and were then randomly assigned to two conditions. In the experimental condition participants read a scientific abstract on the importance of thought control whilst those in the control condition read a neutral abstract. All participants identified a loved person and imagined feeling the impulse to stab this person, then completed again OT beliefs measures (Overimportance of Thought, Moral-Thought Action Fusion and Thought Action Fusion Likelihood). RESULTS: The Moral component of the Thought Action Fusion was reduced by reading a brief text about the possibility and desirability of thought control. However, experimentally induced changes in beliefs did not yield differences in the intrusiveness of the aggressive impulse. CONCLUSIONS: Some beliefs can be modified through a single session in which information similar to what could be obtained in quotidian life is provided.

Management of incidental gallbladder cancer in a national cohort.

BACKGROUND: Incidental gallbladder cancer is a rare event, and its prognosis is largely affected by the tumour stage and treatment. The aim of this study was to analyse the management, treatment and survival of patients with incidental gallbladder cancer in a national cohort over a decade. METHODS: Patients were identified through the Swedish Registry of Gallstone Surgery (GallRiks). Data were cross-linked to the national registry for liver surgery (SweLiv) and the Cancer Registry. Medical records were collected if registry data were missing. Survival was measured as disease-specific survival. The study was divided into two intervals (2007-2011 and 2012-2016) to evaluate changes over time. RESULTS: In total, 249 patients were identified with incidental gallbladder cancer, of whom 92 (36·9 per cent) underwent re-resection with curative intent. For patients with pT2 and pT3 disease, median disease-specific survival improved after re-resection (12·4 versus 44·1 months for pT2, and 9·7 versus 23·0 months for pT3). Residual disease was present in 53 per cent of patients with pT2 tumours who underwent re-resection; these patients had a median disease-specific survival of 32·2 months, whereas the median was not reached in patients without residual disease. Median survival increased by 11 months for all patients between the early and late periods (P = 0·030). CONCLUSION: Re-resection of pT2 and pT3 incidental gallbladder cancer was associated with improved survival, but survival was impaired when residual disease was present. A higher re-resection rate and more R0 resections in the later time period may have been associated with improved survival.

Neurofilament light chain levels in pregnant multiple sclerosis patients: a prospective cohort study.

BACKGROUND AND PURPOSE: Neurofilament light chain is a cytoskeletal protein of neurons. Its levels are increasingly recognized as measures of neuroaxonal damage. The aim of this study was to explore serum neurofilament light chain (sNfL) levels in multiple sclerosis (MS) patients and healthy controls during pregnancy and puerperium. METHODS: This was a prospective, longitudinal, single-center study. sNfL concentration was assessed using a highly sensitive single-molecule array during pregnancy and in puerperium, in a cohort of 39 pregnant patients with relapsing multiple sclerosis (P-MS). Twenty-one healthy pregnant women (HPW) served as a control group. Eight P-MS suffered relapses during pregnancy (P-MS-R) in the first or second trimesters. RESULTS: No differences in pregnancy and delivery data were observed between P-MS and HPW. P-MS showed higher sNfL values than HPW in the first trimester, independently of the presence (P = 0.002) or not (P = 0.02) of relapses during pregnancy. However, in the third trimester, only P-MS-R showed higher sNfL values than HPW (P = 0.001). These differences extended to the puerperium, where P-MS-R showed higher sNfL values than those with no relapses during gestation (P = 0.02). CONCLUSION: These data strongly suggest that sNfL levels reflect MS activity during pregnancy. Additionally, the absence of relapses during pregnancy may have a beneficial effect on neurodegeneration during puerperium.

Inventory of Extended-Spectrum-ß-Lactamase-Producing Enterobacteriaceae in France as Assessed by a Multicenter Study.

The objective of this study was to perform an inventory of the extended-spectrum-ß-lactamase (ESBL)-producing Enterobacteriaceae isolates responsible for infections in French hospitals and to assess the mechanisms associated with ESBL diffusion. A total of 200 nonredundant ESBL-producing Enterobacteriaceae strains isolated from clinical samples were collected during a multicenter study performed in 18 representative French hospitals. Antibiotic resistance genes were identified by PCR and sequencing experiments. The clonal relatedness between isolates was investigated by the use of the DiversiLab system. ESBL-encoding plasmids were compared by PCR-based replicon typing and plasmid multilocus sequence typing. CTX-M-15, CTX-M-1, CTX-M-14, and SHV-12 were the most prevalent ESBLs (8% to 46.5%). The three CTX-M-type EBSLs were significantly observed in Escherichia coli (37.1%, 24.2%, and 21.8%, respectively), and CTX-M-15 was the predominant ESBL in Klebsiella pneumoniae (81.1%). SHV-12 was associated with ESBL-encoding Enterobacter cloacae strains (37.9%). qnrB, aac(6')-Ib-cr, and aac(3)-II genes were the main plasmid-mediated resistance genes, with prevalences ranging between 19.5% and 45% according to the ESBL results. Molecular typing did not identify wide clonal diffusion. Plasmid analysis suggested the diffusion of low numbers of ESBL-encoding plasmids, especially in K. pneumoniae and E. cloacae However, the ESBL-encoding genes were observed in different plasmid replicons according to the bacterial species. The prevalences of ESBL subtypes differ according to the Enterobacteriaceae species. Plasmid spread is a key determinant of this epidemiology, and the link observed between the ESBL-encoding plasmids and the bacterial host explains the differences observed in the Enterobacteriaceae species.

Prostate cancer.

Much progress has been made in research for prostate cancer in the past decade. There is now greater understanding for the genetic basis of familial prostate cancer with identification of rare but high-risk mutations (eg, BRCA2, HOXB13) and low-risk but common alleles (77 identified so far by genome-wide association studies) that could lead to targeted screening of patients at risk. This is especially important because screening for prostate cancer based on prostate-specific antigen remains controversial due to the high rate of overdiagnosis and unnecessary prostate biopsies, despite evidence that it reduces mortality. Classification of prostate cancer into distinct molecular subtypes, including mutually exclusive ETS-gene-fusion-positive and SPINK1-overexpressing, CHD1-loss cancers, could allow stratification of patients for different management strategies. Presently, men with localised disease can have very different prognoses and treatment options, ranging from observation alone through to radical surgery, with few good-quality randomised trials to inform on the best approach for an individual patient. The survival of patients with metastatic prostate cancer progressing on androgen-deprivation therapy (castration-resistant prostate cancer) has improved substantially. In addition to docetaxel, which has been used for more than a decade, in the past 4 years five new drugs have shown efficacy with improvements in overall survival leading to licensing for the treatment of metastatic castration-resistant prostate cancer. Because of this rapid change in the therapeutic landscape, no robust data exist to inform on the selection of patients for a specific treatment for castration-resistant prostate cancer or the best sequence of administration. Moreover, the high cost of the newer drugs limits their widespread use in several countries. Data from continuing clinical and translational research are urgently needed to improve, and, crucially, to personalise management.

Endovascular treatment of cerebral venous sinus thrombosis (CVST): Is a complete recanalization required for a good clinical outcome?

The usual therapy in cerebral venous sinus thrombosis (CVST) is based on anticoagulant treatment with adjusted-dose unfractionated heparin. When medical treatment fails, endovascular techniques, such as mechanical thrombectomy, are available. We report a case of a 21-year-old woman with a diagnosis of left CVST, treated by a neurointerventional approach with mechanical thrombectomy using the Penumbra(®) System. Despite the fact that only incomplete recanalization was achieved, a gradual resolution of the thrombus and a progressive clinical improvement occurred.

Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in 1 of 3 genes. In the 60% of patients who are mutation negative, we have recently shown that the clinical phenotype can be associated with an accumulation of common small-effect LDL cholesterol (LDL-C)-raising alleles by use of a 12-single nucleotide polymorphism (12-SNP) score. The aims of the study were to improve the selection of SNPs and replicate the results in additional samples. METHODS: We used ROC curves to determine the optimum number of LDL-C SNPs. For replication analysis, we genotyped patients with a clinical diagnosis of FH from 6 countries for 6 LDL-C-associated alleles. We compared the weighted SNP score among patients with no confirmed mutation (FH/M-), those with a mutation (FH/M+), and controls from a UK population sample (WHII). RESULTS: Increasing the number of SNPs to 33 did not improve the ability of the score to discriminate between FH/M- and controls, whereas sequential removal of SNPs with smaller effects/lower frequency showed that a weighted score of 6 SNPs performed as well as the 12-SNP score. Metaanalysis of the weighted 6-SNP score, on the basis of polymorphisms in CELSR2 (cadherin, EGF LAG 7-pass G-type receptor 2), APOB (apolipoprotein B), ABCG5/8 [ATP-binding cassette, sub-family G (WHITE), member 5/8], LDLR (low density lipoprotein receptor), and APOE (apolipoprotein E) loci, in the independent FH/M- cohorts showed a consistently higher score in comparison to the WHII population (P < 2.2 × 10(-16)). Modeling in individuals with a 6-SNP score in the top three-fourths of the score distribution indicated a >95% likelihood of a polygenic explanation of their increased LDL-C. CONCLUSIONS: A 6-SNP LDL-C score consistently distinguishes FH/M- patients from healthy individuals. The hypercholesterolemia in 88% of mutation-negative patients is likely to have a polygenic basis.

Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations.

BACKGROUND: Familial hypercholesterolaemia (FH) is an autosomal dominant disease of lipid metabolism, which leads to early coronary heart disease. Mutations in LDLR, APOB and PCSK9 can be detected in 80% of definite FH (DFH) patients. This study aimed to identify novel FH-causing genetic variants in patients with no detectable mutation. METHODS AND RESULTS: Exomes of 125 unrelated DFH patients were sequenced, as part of the UK10K project. First, analysis of known FH genes identified 23 LDLR and two APOB mutations, and patients with explained causes of FH were excluded from further analysis. Second, common and rare variants in genes associated with low-density lipoprotein cholesterol (LDL-C) levels in genome-wide association study (GWAS) meta-analysis were examined. There was no clear rare variant association in LDL-C GWAS hits; however, there were 29 patients with a high LDL-C SNP score suggestive of polygenic hypercholesterolaemia. Finally, a gene-based burden test for an excess of rare (frequency <0.005) or novel variants in cases versus 1926 controls was performed, with variants with an unlikely functional effect (intronic, synonymous) filtered out. CONCLUSIONS: No major novel locus for FH was detected, with no gene having a functional variant in more than three patients; however, an excess of novel variants was found in 18 genes, of which the strongest candidates included CH25H and INSIG2 (p<4.3×10(-4) and p<3.7×10(-3), respectively). This suggests that the genetic cause of FH in these unexplained cases is likely to be very heterogeneous, which complicates the diagnostic and novel gene discovery process.

Functional group directed C-H borylation.

The direct borylation of hydrocarbons via C-H activation has reached an impressive level of sophistication and efficiency, emerging as a fundamental tool in synthesis because of the versatility offered by organoboron compounds. As a remarkable particularity, the catalytic systems originally developed for these reactions are relatively insensitive to directing effects, and the regioselectivity of the borylations is typically governed by steric factors. Likely stimulated by the great synthetic potential of the expected functionalised organoboranes, however, many groups have recently focused on the development of complementary strategies for directed, site-selective borylation reactions where a directing group controls the course of the reaction. In this tutorial review, the different strategies and findings related to the development of these directed borylation reactions via C(sp(2))-H or C(sp(3))-H activation will be summarized and discussed.

Electron and ion temperature measurement with a new x-ray imaging crystal spectrometer on WEST.

A new x-ray imaging crystal spectrometer (XICS) has been installed, aligned, and used during experimental campaigns on the WEST tokamak. It has three interchangeable crystals for measuring the Ar XVII, Ar XVIII, and Fe XXV spectra, respectively. A patented rotating table holding the crystals is used to monitor the crystal facing the plasma remotely and without changing the position of the camera. Here, the focus is made on the Ar XVII spectrum, between 3.93 and 4.00 Å. The design of the diagnostic is presented, and a synthetic diagnostic, implemented with the Python library ToFu, is used to show the instrument's operational performance and limits. The instrument function exhibits the following two main features: a distortion for the Ar XVII spectrum, presumably due to the crystal manufacturing in two parts, and the measurement of three W spectral lines on the Ar XVI spectrum. Line of sight-integrated profiles of the electron and ion temperatures are thus extracted from the Ar XVII spectrum from two distinct spectral line ratios and from the Doppler broadening, respectively. The bremsstrahlung emission and the W line measurements are the two main limitations to compute the electron temperature. Tomographic inversions are also implemented with the library ToFu and used in order to obtain the local electron and ion temperature profiles, which are compared to other measurements from the WEST ECE (electron cyclotron emission) diagnostic. It is shown that both the XICS line-integrated and ECE Te measurements are in better agreement. Systematic differences are shown between the electron temperature profiles calculated from the two available line ratios.

Gamma-ray sources imaging and test-beam results with MACACO III Compton camera.

Hadron therapy is a radiotherapy modality which offers a precise energy deposition to the tumors and a dose reduction to healthy tissue as compared to conventional methods. However, methods for real-time monitoring are required to ensure that the radiation dose is deposited on the target. The IRIS group of IFIC-Valencia developed a Compton camera prototype for this purpose, intending to image the Prompt Gammas emitted by the tissue during irradiation. The system detectors are composed of Lanthanum (III) bromide scintillator crystals coupled to silicon photomultipliers. After an initial characterization in the laboratory, in order to assess the system capabilities for future experiments in proton therapy centers, different tests were carried out in two facilities: PARTREC (Groningen, The Netherlands) and the CNA cyclotron (Sevilla, Spain). Characterization studies performed at PARTREC indicated that the detectors linearity was improved with respect to the previous version and an energy resolution of 5.2 % FWHM at 511 keV was achieved. Moreover, the imaging capabilities of the system were evaluated with a line source of 68Ge and a point-like source of 241Am-9Be. Images at 4.439 MeV were obtained from irradiation of a graphite target with an 18 MeV proton beam at CNA, to perform a study of the system potential to detect shifts at different intensities. In this sense, the system was able to distinguish 1 mm variations in the target position at different beam current intensities for measurement times of 1800 and 600 s.

Reduction of the use of antimicrobial drugs following the rapid detection of Streptococcus agalactiae in the vagina at delivery by real-time PCR assay.

OBJECTIVE: To assess whether the determination of the presence of group B streptococci (GBS) in the vagina using a rapid polymerase chain reaction (PCR) assay at delivery was able to spare useless antimicrobial treatments, as compared with conventional culture at 34-38 weeks of gestation. DESIGN: Practical evaluation and prospective cost-effectiveness analysis. SETTING: A university hospital in France. POPULATION: A cohort of 225 women in labour at the University-Hospital of Saint-Etienne. METHODS: Each woman had a conventional culture performed at 34-38 weeks of gestation. At the beginning of labour, two vaginal swabs were sampled for rapid PCR testing and culture. The decision to prescribe a prophylactic antimicrobial treatment or not was taken according to the result of the PCR test. A comparative cost-effectiveness analysis of the two diagnostic strategies was carried out. MAIN OUTCOME MEASURES: Number of women receiving inadequate prophylactic antimicrobial drugs following each testing strategy, costs of PCR testing and culture, frequency of vaginal GBS, and diagnostic performance of the PCR test at delivery. RESULTS: The percentage of unnecessarily treated women was significantly reduced using the rapid test versus conventional culture (4.5 and 13.6%, respectively; P < 0.001). The rate of vaginal GBS at delivery was 12.5%. The incremental cost-effectiveness ratio (ICER) for each inadequate management avoided was €36 and €173 from the point of view of the healthcare system and hospital, respectively. CONCLUSIONS: The PCR assay reduced the number of inadequate antimicrobial treatments aimed to prevent the early onset of GBS disease. However, this strategy generates extra costs that must be put into balance with its clinical benefits.

Use of targeted exome sequencing as a diagnostic tool for Familial Hypercholesterolaemia.

BACKGROUND: Familial Hypercholesterolaemia (FH) is an autosomal dominant disease, caused by mutations in LDLR, APOB or PCSK9, which results in high levels of LDL-cholesterol (LDL-C) leading to early coronary heart disease. An autosomal recessive form of FH is also known, due to homozygous mutations in LDLRAP1. This study assessed the utility of an exome capture method and deep sequencing in FH diagnosis. METHODS: Exomes of 48 definite FH patients, with no mutation detected by current methods, were captured by Agilent Human All Exon 50Mb assay and sequenced on the Illumina HiSeq 2000 platform. Variants were called by GATK and SAMtools. RESULTS: The mean coverage of FH genes varied considerably (PCSK9=23x, LDLRAP1=36x, LDLR=56x and APOB=93x). Exome sequencing detected 17 LDLR mutations, including three copy number variants, two APOB mutations, missed by the standard techniques, two LDLR novel variants likely to be FH-causing, and five APOB variants of uncertain effect. Two variants called in PCSK9 were not confirmed by Sanger sequencing. One heterozygous mutation was found in LDLRAP1. CONCLUSIONS: High-throughput DNA sequencing demonstrated its efficiency in well-covered DNA regions, in particular LDLR. This highly automated technology is proving to be effective for heterogeneous diseases and may soon replace laborious conventional methods. However, the poor coverage of gene promoters and repetitive, or GC-rich sequences, remains problematic, and validation of all identified variants is currently required.

Influence of the background in Compton camera images for proton therapy treatment monitoring.

Objective. Background events are one of the most relevant contributions to image degradation in Compton camera imaging for hadron therapy treatment monitoring. A study of the background and its contribution to image degradation is important to define future strategies to reduce the background in the system.Approach. In this simulation study, the percentage of different kinds of events and their contribution to the reconstructed image in a two-layer Compton camera have been evaluated. To this end, GATE v8.2 simulations of a proton beam impinging on a PMMA phantom have been carried out, for different proton beam energies and at different beam intensities.Main results. For a simulated Compton camera made of Lanthanum (III) Bromide monolithic crystals, coincidences caused by neutrons arriving from the phantom are the most common type of background produced by secondary radiations in the Compton camera, causing between 13% and 33% of the detected coincidences, depending on the beam energy. Results also show that random coincidences are a significant cause of image degradation at high beam intensities, and their influence in the reconstructed images is studied for values of the time coincidence windows from 500 ps to 100 ns.Significance. Results indicate the timing capabilities required to retrieve the fall-off position with good precision. Still, the noise observed in the image when no randoms are considered make us consider further background rejection methods.

Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment.

Familial hypercholesterolemia (FH) is caused predominately by variants in the low-density lipoprotein receptor gene (LDLR). We report here an update of the UCL LDLR variant database to include variants reported in the literature and in-house between 2008 and 2010, transfer of the database to LOVDv.2.0 platform (https://grenada.lumc.nl/LOVD2/UCL-Heart/home.php?select_db=LDLR) and pathogenicity analysis. The database now contains over 1288 different variants reported in FH patients: 55% exonic substitutions, 22% exonic small rearrangements (<100 bp), 11% large rearrangements (>100 bp), 2% promoter variants, 10% intronic variants and 1 variant in the 3' untranslated sequence. The distribution and type of newly reported variants closely matches that of the 2008 database, and we have used these variants (n= 223) as a representative sample to assess the utility of standard open access software (PolyPhen, SIFT, refined SIFT, Neural Network Splice Site Prediction Tool, SplicePort and NetGene2) and additional analyses (Single Amino Acid Polymorphism database, analysis of conservation and structure and Mutation Taster) for pathogenicity prediction. In combination, these techniques have enabled us to assign with confidence pathogenic predictions to 8/8 in-frame small rearrangements and 8/9 missense substitutions with previously discordant results from PolyPhen and SIFT analysis. Overall, we conclude that 79% of the reported variants are likely to be disease causing.

Six Major Steps to Make Investigations of Suicide Valuable for Learning and Prevention.

OBJECTIVE: The decline in suicide rates has leveled off in many countries during the last decade, suggesting that new interventions are needed in the work with suicide prevention. Learnings from investigations of suicide should contribute to the development of these new interventions. However, reviews of investigations have indicated that few new lessons have been learned. To be an effective tool, revisions of the current investigation methods are required. This review aimed to describe the problems with the current approaches to investigations of suicide as patient harm and to propose ways to move forward. METHODS: Narrative literature review. RESULTS: Several weaknesses in the current approaches to investigations were identified. These include failures in embracing patient and system perspectives, not addressing relevant factors, and insufficient competence of the investigation teams. Investigation methods need to encompass the progress of knowledge about suicidal behavior, suicide prevention, and patient safety. CONCLUSIONS: There is a need for a paradigm shift in the approaches to investigations of suicide as potential patient harm to enable learning and insights valuable for healthcare improvement. Actions to support this paradigm shift include involvement of patients and families, education for investigators, multidisciplinary analysis teams with competence in and access to relevant parts across organizations, and triage of cases for extensive analyses. A new model for the investigation of suicide that support these actions should facilitate this paradigm shift.HIGHLIGHTSThere are weaknesses in the current approaches to investigations of suicide.A paradigm shift in investigations is needed to contribute to a better understanding of suicide.New knowledge of suicidal behavior, prevention, and patient safety must be applied.