A comparison of two tests for filarial antigenemia in areas in Sri Lanka and Indonesia with low-level persistence of lymphatic filariasis following mass drug administration

BACKGROUND: Filarial antigen tests are key tools for mapping the distribution of bancroftian filariasis and for detecting areas with persistent infections following mass drug administration (MDA). A recent study showed that the new Alere Filariasis Test Strip (FTS) has better analytical sensitivity than the BinaxNOW Filariasis card test (Card Test) for detecting circulating filarial antigen, and the FTS detected more positive results than the Card Test in a field study performed in a highly endemic area in Liberia. METHODS: The present study compared the performance of the FTS and the Card Test in community surveys that were conducted in southern Sri Lanka and in Indonesia (Central Java) in areas with low-level persistence of LF following multiple rounds of MDA with diethylcarbamazine plus albendazole. The studies were performed in densely populated semi-urban areas where Wuchereria bancrofti is transmitted by Culex quinquefasciatus. RESULTS: Antigenemia rates by FTS were 138 % higher in the Sri Lanka study (43/852 vs. 18/852) and 21 % higher in the Indonesia study (50/778 vs. 41/778) than antigenemia rates by Card Test. Antigenemia rates were significantly higher in males than in females and higher in adults than in children in both study sites. Although overall antigenemia rates and test scores were significantly higher by FTS than by Card Test in both study areas, rates in young children were similar with both tests in both areas. CONCLUSIONS: These results extend the previously reported superior sensitivity of the FTS to areas with low residual infection rates following MDA, and this could affect mapping and post-MDA survey results in adults. However, our findings suggest that results of transmission assessment surveys (TAS) performed in school-aged children are likely to be similar with both tests

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

Background: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. Methods: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. Results: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers. Conclusion: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. A Osorio1, R L Milne2, G Pita3, P Peterlongo4,5, T Heikkinen6, J Simard7, G Chenevix-Trench8, A B Spurdle8, J Beesley8, X Chen8, S Healey8, KConFab9, S L Neuhausen10, Y C Ding10, F J Couch11,12, X Wang11, N Lindor13, S Manoukian4, M Barile14, A Viel15, L Tizzoni5,16, C I Szabo17, L Foretova18, M Zikan19, K Claes20, M H Greene21, P Mai21, G Rennert22, F Lejbkowicz22, O Barnett-Griness22, I L Andrulis23,24, H Ozcelik24, N Weerasooriya23, OCGN23, A-M Gerdes25, M Thomassen25, D G Cruger26, M A Caligo27, E Friedman28,29, B Kaufman28,29, Y Laitman28, S Cohen28, T Kontorovich28, R Gershoni-Baruch30, E Dagan31,32, H Jernström33, M S Askmalm34, B Arver35, B Malmer36, SWE-BRCA37, S M Domchek38, K L Nathanson38, J Brunet39, T Ramón y Cajal40, D Yannoukakos41, U Hamann42, HEBON37, F B L Hogervorst43, S Verhoef43, EB Gómez García44,45, J T Wijnen46,47, A van den Ouweland48, EMBRACE37, D F Easton49, S Peock49, M Cook49, C T Oliver49, D Frost49, C Luccarini50, D G Evans51, F Lalloo51, R Eeles52, G Pichert53, J Cook54, S Hodgson55, P J Morrison56, F Douglas57, A K Godwin58, GEMO59,60,61, O M Sinilnikova59,60, L Barjhoux59,60, D Stoppa-Lyonnet61, V Moncoutier61, S Giraud59, C Cassini62,63, L Olivier-Faivre62,63, F Révillion64, J-P Peyrat64, D Muller65, J-P Fricker65, H T Lynch66, E M John67, S Buys68, M Daly69, J L Hopper70, M B Terry71, A Miron72, Y Yassin72, D Goldgar73, Breast Cancer Family Registry37, C F Singer74, D Gschwantler-Kaulich74, G Pfeiler74, A-C Spiess74, Thomas v O Hansen75, O T Johannsson76, T Kirchhoff77, K Offit77, K Kosarin77, M Piedmonte78, G C Rodriguez79, K Wakeley80, J F Boggess81, J Basil82, P E Schwartz83, S V Blank84, A E Toland85, M Montagna86, C Casella87, E N Imyanitov88, A Allavena89, R K Schmutzler90, B Versmold90, C Engel91, A Meindl92, N Ditsch93, N Arnold94, D Niederacher95, H Deißler96, B Fiebig97, R Varon-Mateeva98, D Schaefer99, U G Froster100, T Caldes101, M de la Hoya101, L McGuffog49, A C Antoniou49, H Nevanlinna6, P Radice4,5 and J Benítez1,3 on behalf of CIMB

(5′S)-8,5′-Cyclo-2′-deoxyguanosine Is a Strong Block to Replication, a Potent pol V-Dependent Mutagenic Lesion, and Is Inefficiently Repaired in Escherichia coli

8,5′-Cyclopurines, making up an important class of ionizing radiation-induced tandem DNA damage, are repaired only by nucleotide excision repair (NER). They accumulate in NER-impaired cells, as in Cockayne syndrome group B and certain Xeroderma Pigmentosum patients. A plasmid containing (5′S)-8,5′-cyclo-2′-deoxyguanosine (S-cdG) was replicated in Escherichia coli with specific DNA polymerase knockouts. Viability was \u3c1% in the wild-type strain, which increased to 5.5% with SOS. Viability decreased further in a pol II- strain, whereas it increased considerably in a pol IV- strain. Remarkably, no progeny was recovered from a pol V- strain, indicating that pol V is absolutely required for bypassing S-cdG. Progeny analyses indicated that S-cdG is significantly mutagenic, inducing ∼34% mutation with SOS. Most mutations were S-cdG → A mutations, though S-cdG → T mutation and deletion of 5′C also occurred. Incisions of purified UvrABC nuclease on S-cdG, S-cdA, and C8-dG-AP on a duplex 51-mer showed that the incision rates are C8-dG-AP \u3e S-cdA \u3e S-cdG. In summary, S-cdG is a major block to DNA replication, highly mutagenic, and repaired slowly in E. coli

A Community-Based Study of Factors Associated with Continuing Transmission of Lymphatic Filariasis in Leogane, Haiti

Seven rounds of mass drug administration (MDA) have been administered in Leogane, Haiti, an area hyperendemic for lymphatic filariasis (LF). Sentinel site surveys showed that the prevalence of microfilaremia was reduced to <1% from levels as high as 15.5%, suggesting that transmission had been reduced. A separate 30-cluster survey of 2- to 4-year-old children was conducted to determine if MDA interrupted transmission. Antigen and antifilarial antibody prevalence were 14.3% and 19.7%, respectively. Follow-up surveys were done in 6 villages, including those selected for the cluster survey, to assess risk factors related to continued LF transmission and to pinpoint hotspots of transmission. One hundred houses were mapped in each village using GPS-enabled PDAs, and then 30 houses and 10 alternates were chosen for testing. All individuals in selected houses were asked to participate in a short survey about participation in MDA, history of residence in Leogane and general knowledge of LF. Survey teams returned to the houses at night to collect blood for antigen testing, microfilaremia and Bm14 antibody testing and collected mosquitoes from these communities in parallel. Antigen prevalence was highly variable among the 6 villages, with the highest being 38.2% (Dampus) and the lowest being 2.9% (Corail Lemaire); overall antigen prevalence was 18.5%. Initial cluster surveys of 2- to 4-year-old children were not related to community antigen prevalence. Nearest neighbor analysis found evidence of clustering of infection suggesting that LF infection was focal in distribution. Antigen prevalence among individuals who were systematically noncompliant with the MDAs, i.e. they had never participated, was significantly higher than among compliant individuals (p<0.05). A logistic regression model found that of the factors examined for association with infection, only noncompliance was significantly associated with infection. Thus, continuing transmission of LF seems to be linked to rates of systematic noncompliance

Rapid automatic segmentation of abnormal tissue in late gadolinium enhancement cardiovascular magnetic resonance images for improved management of long-standing persistent atrial fibrillation

Background: Atrial fibrillation (AF) is the most common heart rhythm disorder. In order for late Gd enhancement cardiovascular magnetic resonance (LGE CMR) to ameliorate the AF management, the ready availability of the accurate enhancement segmentation is required. However, the computer-aided segmentation of enhancement in LGE CMR of AF is still an open question. Additionally, the number of centres that have reported successful application of LGE CMR to guide clinical AF strategies remains low, while the debate on LGE CMR’s diagnostic ability for AF still holds. The aim of this study is to propose a method that reliably distinguishes enhanced (abnormal) from non-enhanced (healthy) tissue within the left atrial wall of (pre-ablation and 3 months post-ablation) LGE CMR data-sets from long-standing persistent AF patients studied at our centre. Methods: Enhancement segmentation was achieved by employing thresholds benchmarked against the statistics of the whole left atrial blood-pool (LABP). The test-set cross-validation mechanism was applied to determine the input feature representation and algorithm that best predict enhancement threshold levels. Results: Global normalized intensity threshold levels T PRE = 1 1/4 and T POST = 1 5/8 were found to segment enhancement in data-sets acquired pre-ablation and at 3 months post-ablation, respectively. The segmentation results were corroborated by using visual inspection of LGE CMR brightness levels and one endocardial bipolar voltage map. The measured extent of pre-ablation fibrosis fell within the normal range for the specific arrhythmia phenotype. 3D volume renderings of segmented post-ablation enhancement emulated the expected ablation lesion patterns. By comparing our technique with other related approaches that proposed different threshold levels (although they also relied on reference regions from within the LABP) for segmenting enhancement in LGE CMR data-sets of AF patients, we illustrated that the cut-off levels employed by other centres may not be usable for clinical studies performed in our centre. Conclusions: The proposed technique has great potential for successful employment in the AF management within our centre. It provides a highly desirable validation of the LGE CMR technique for AF studies. Inter-centre differences in the CMR acquisition protocol and image analysis strategy inevitably impede the selection of a universally optimal algorithm for segmentation of enhancement in AF studies

Biliary atresia

Biliary atresia (BA) is a rare disease characterised by a biliary obstruction of unknown origin that presents in the neonatal period. It is the most frequent surgical cause of cholestatic jaundice in this age group. BA occurs in approximately 1/18,000 live births in Western Europe. In the world, the reported incidence varies from 5/100,000 to 32/100,000 live births, and is highest in Asia and the Pacific region. Females are affected slightly more often than males. The common histopathological picture is one of inflammatory damage to the intra- and extrahepatic bile ducts with sclerosis and narrowing or even obliteration of the biliary tree. Untreated, this condition leads to cirrhosis and death within the first years of life. BA is not known to be a hereditary condition. No primary medical treatment is relevant for the management of BA. Once BA suspected, surgical intervention (Kasai portoenterostomy) should be performed as soon as possible as operations performed early in life is more likely to be successful. Liver transplantation may be needed later if the Kasai operation fails to restore the biliary flow or if cirrhotic complications occur. At present, approximately 90% of BA patients survive and the majority have normal quality of life

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

withdrawn 2017 hrs ehra ecas aphrs solaece expert consensus statement on catheter and surgical ablation of atrial fibrillation

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