Cost-effectiveness of expanded latent TB infection testing and treatment: Lynn City, Massachusetts, USA.

BACKGROUND: Between October 2016 and March 2019, Lynn Community Health Center in Massachusetts implemented a targeted latent TB infection testing and treatment (TTT) program, increasing testing from a baseline of 1,200 patients tested to an average of 3,531 patients tested, or 9% of the population per year.METHODS: We compared pre-implementation TTT, represented by the first two quarters of implementation data, to TTT, represented by 12 quarters of data. Time, diagnostic, and laboratory resources were estimated using micro-costing. Other cost and testing data were obtained from the electronic health record, pharmaceutical claims, and published reimbursement rates. A Markov cohort model estimated future health outcomes and cost-effectiveness from a societal perspective in 2020 US dollars. Monte Carlo simulation generated 95% uncertainty intervals.RESULTS: The TTT program exhibited extended dominance over baseline pre-intervention testing and had an incremental cost-effectiveness ratio (ICER) of US$52,603 (US$22,008â-"US$95,360). When compared to baseline pre-TTT testing, the TTT program averted an estimated additional 7.12 TB cases, 3.49 hospitalizations, and 0.16 deaths per lifetime cohort each year.CONCLUSIONS: TTT was more cost-effective than baseline pre-implementation testing. Lynn Community Health Centerâ-™s experience can help inform other clinics considering expanding latent TB infection testing.

Implications of Dedicated Seismometer Measurements on Newtonian-Noise Cancellation for Advanced LIGO.

Newtonian gravitational noise from seismic fields will become a limiting noise source at low frequency for second-generation, gravitational-wave detectors. It is planned to use seismic sensors surrounding the detectors' test masses to coherently subtract Newtonian noise using Wiener filters derived from the correlations between the sensors and detector data. In this Letter, we use data from a seismometer array deployed at the corner station of the Laser Interferometer Gravitational Wave Observatory (LIGO) Hanford detector combined with a tiltmeter for a detailed characterization of the seismic field and to predict achievable Newtonian-noise subtraction levels. As was shown previously, cancellation of the tiltmeter signal using seismometer data serves as the best available proxy of Newtonian-noise cancellation. According to our results, a relatively small number of seismometers is likely sufficient to perform the noise cancellation due to an almost ideal two-point spatial correlation of seismic surface displacement at the corner station, or alternatively, a tiltmeter deployed under each of the two test masses of the corner station at Hanford will be able to efficiently cancel Newtonian noise. Furthermore, we show that the ground tilt to differential arm-length coupling observed during LIGO's second science run is consistent with gravitational coupling.

Analysis of the cox1 gene in Echinococcus granulosus from sheep in northeast Iran using PCR high-resolution melting (qPCR-HRM) curve analysis.

Echinococcus granulosus, the etiologic agent of echinococcosis, is one of the most important zoonotic helminthes worldwide. Knowledge of E. granulosus species and genotypes has important implications for epidemiology, control, and prevention of diseases as well as future vaccine and drug designs. There are many molecular methods developed to define genotypes of E. granulosus, among them high resolution melting (HRM) analysis, as a new approach, is a single step and closed tube method. It is appropriate for fast screening of large number of isolates. This technique is an accurate, user friendly, cost-effective, fast and simple method, which does not need post-PCR processes. Between March and lst august 2016, of 726 sheep examined in abattoirs in Razavi Khorasan province, Northeast Iran, 109 harboured cystic echincoccosis lesions (liver samples= 65 and lung samples= 44) which were collected for analysis. Total genomic DNA was extracted from each sample and amplified for the presence of polymorphism in the mitochondrial cox1 gene of Echinococcus granulosus using a high resolution melting curve (HRM) method. A total of 109 hydatid cyst samples analyzed by PCR high-resolution melting (qPCR-HRM) curve of the cox1 gene, all isolates were identified as G1 genotype (sheep strain). G1 is the predominant genotype in sheep in northeast of Iran. The high incidence of the G1 genotype (known to be the predominant E. granulosus genotype infecting humans globally) in sheep has considerable implications for hydatid disease control programs in this area.

Surgical treatment of hepatic cystic echinococcosis in patients co-infected with HIV/AIDS.

Co-infections of cystic echinococcosis (CE) and HIV/AIDS is rare. We report four CE cases that were HIV positive. Three out of the four patients underwent a surgical operation to remove the hydatid cysts in their livers. The operation confirmed that in two of the cases their cysts had ruptured. These patients were given 3 months of albendazole after the operation. Follow-up showed they were remarkably improved in term of their health, although they were still HIV antibody positive 6 months after surgical treatment. Interestingly, the treatment remarkably increased their CD4+ cell population. We showed that surgery is suitable for treating hepatic cystic echinococcosis with HIV/AIDS co-infection.

A cross sectional study of p504s, CD133, and Twist expression in the esophageal metaplasia dysplasia adenocarcinoma sequence.

The incidence of esophageal adenocarcinoma has increased dramatically over recent years and Barrett's esophagus is considered the most established risk factor for its development. Endoscopic surveillance of Barrett's esophagus is therefore recommended but hinges on histological interpretation of randomly taken biopsies which is poorly reproducible. The use of biomarkers presents an opportunity to improve our ability to risk-stratify these patients.We examined three biomarkers namely p504s, CD133, and Twist in the setting of Barrett's esophagus, low-grade dysplasia, and esophageal adenocarcinoma to evaluate differential expression between benign, dysplastic, and malignant Barrett's tissue in an exploratory cross-sectional study. Twenty-five cases each of Barrett's esophagus, low-grade dysplasia, and esophageal adenocarcinoma were included along-with 25 cases of esophagectomy resections for Barrett's adenocarcinoma. The biomarkers were immunostained on automated Ventana(®) immunostainer. The biopsies were assessed for biomarker expression by two independent observers. Granular cytoplasmic staining of p504s was observed in dysplastic Barrett's biopsies and esophageal adenocarcinoma but not in Barrett's esophagus. Apical and membranous CD133 expression was also observed in dysplastic Barrett's and esophageal adenocarcinoma. Nuclear Twist expression was seen predominantly in stromal cells. There was increased p504s expression in dysplastic Barrett's esophagus and esophageal adenocarcinoma compared with controls. CD133 expression was detected for the first time in esophageal adenocarcinoma and dysplastic Barrett's esophagus. Twist expression was not convincing enough to be labeled as Barrett's biomarker. p504s and CD133 have the potential to differentiate benign from malignant Barrett's tissue in this exploratory study. Their validity should be established in prospective longitudinal studies.

Epstein-Barr virus positive inflammatory pseudo-tumour of the spleen: A case report and literature review.

INTRODUCTION: Epstein-Barr virus positive inflammatory pseudo-tumour (IPT) of the spleen is an uncommon, frequently asymptomatic entity, which is typically picked up as an incidental finding on imaging. PRESENTATION OF CASE: We present a case of EBV positive IPT of the spleen which presented as an incidental finding on CT in a patient with a history of malignancy. Splenectomy was performed. DISCUSSION: IPTs are benign spindle cell lesions of varying aetiology, which can arise in a variety of tissues, including the spleen. In situ hybridisation showed strong staining for Epstein-Barr virus RNA in our case, in common with many similar lesions described in the literature. The differential diagnosis of such spindle cell tumours is discussed. CONCLUSION: Radiologically, EBV positive spindle cell tumours are indistinguishable from malignant lesions such as lymphoma and diagnosis is made on histology, usually at splenectomy.

Integrating molecular diagnostics into histopathology training: the Belfast model.

Molecular medicine is transforming modern clinical practice, from diagnostics to therapeutics. Discoveries in research are being incorporated into the clinical setting with increasing rapidity. This transformation is also deeply changing the way we practise pathology. The great advances in cell and molecular biology which have accelerated our understanding of the pathogenesis of solid tumours have been embraced with variable degrees of enthusiasm by diverse medical professional specialties. While histopathologists have not been prompt to adopt molecular diagnostics to date, the need to incorporate molecular pathology into the training of future histopathologists is imperative. Our goal is to create, within an existing 5-year histopathology training curriculum, the structure for formal substantial teaching of molecular diagnostics. This specialist training has two main goals: (1) to equip future practising histopathologists with basic knowledge of molecular diagnostics and (2) to create the option for those interested in a subspecialty experience in tissue molecular diagnostics to pursue this training. It is our belief that this training will help to maintain in future the role of the pathologist at the centre of patient care as the integrator of clinical, morphological and molecular information.

Immunodiagnosis of sheep infections with Echinococcus granulosus: in 35 years where have we come?

W. K. Yong and D. D. Heath published in 1979 a seminal paper in the first issue of Parasite immunology describing their efforts to determine whether the arc 5 precipitin band, formed when test human serum is reacted against electrophoresed hydatid cyst fluid antigen, would be a suitable immunodiagnostic test for the identification of sheep infected with Echinococcus granulosus. Although they found antibodies to arc 5 in the sera of hydatid-infected sheep, the sera of some sheep harbouring Taenia ovis and T. hydatigena also precipitated the hydatid cyst fluid arc 5 antigen, so they concluded arc 5 antibodies were not suitable for the specific immunodiagnosis of E. granulosus infection in sheep in New Zealand. Subsequent work has shown that the existence of multiple infections with different taeniid species, antigenic cross-reactivity between these related parasites and the low level of specific antibody response to infection continue to hinder efforts to improve the diagnosis of hydatid infection in sheep and other natural intermediate hosts, thereby preventing the development of any practical test. In particular, the poor antibody response of ruminants to naturally acquired hydatid infection may prove an insurmountable barrier in future efforts to develop a reliable and accurate immunological test.

Current status of the genetics and molecular taxonomy of Echinococcus species.

The taxonomy of Echinococcus has long been controversial. Based mainly on differences in morphology and host-parasite specificity characteristics, 16 species and 13 subspecies were originally described. Subsequently, most of these taxa were regarded as synonyms for Echinococcus granulosus and only 4 valid species were recognised: E. granulosus; E. multilocularis; E. oligarthrus and E. vogeli. But, over the past 50 years, laboratory and field observations have revealed considerable phenotypic variability between isolates of Echinococcus, particularly those of E. granulosus, which include differences in: morphology in both larval and adult stages, development in vitro and in vivo, host infectivity and specificity, chemical composition, metabolism, proteins and enzymes, pathogenicity and antigenicity. The application of molecular tools has revealed differences in nucleic acid sequences that reflect this phenotypic variation and the genetic and phenotypic characteristics complement the previous observations made by the descriptive parasitologists many years ago. The fact that some of these variants or strains are poorly or not infective to humans has resulted in a reappraisal of the public health significance of Echinococcus in areas where such variants occur. A revised taxonomy for species in the Echinococcus genus has been proposed that is generally accepted, and is based on the new molecular data and the biological and epidemiological characteristics of host-adapted species and strains.

Novel immunomic technologies for schistosome vaccine development.

Schistosomiasis remains one of the most common human helminthiases, despite the availability of an effective drug against the causative parasites. Drug treatment programmes have several limitations, and it is likely that a vaccine is required for effective control. While decades of vaccine development have seen the discovery and testing of several candidate antigens, none have shown consistent and acceptable high levels of protection. The migrating larval stages are susceptible to immunity, however few larval-specific antigens have been discovered. Therefore, there is a need to identify novel larval-specific antigens, which may prove to be more efficacious than existing targets. Immunomics, a relatively new field developed to cope with the recent large influx of biological information, holds promise for the discovery of vaccine targets, and this review highlights some immunomic approaches to schistosome vaccine development. Firstly, a method to focus on the immune response elicited by the important and vulnerable larval stage is described, which allows a targeted study of the immunome at different tissue sites. Then, two high-throughput arrays are discussed for the identification of protein and carbohydrate antigens. It is anticipated that these approaches will progress vaccine development against the schistosomes, as well as other parasites.

A hidden cause of upper gastrointestinal bleeding.

Gastrointestinal stromal tumours (GISTs) are a subset of gastrointestinal (GI) mesenchymal tumours of varying differentiation and represent 1-3% of all gastrointestinal malignancies--70% occur in the stomach. Previously, these tumours were classified as GI leiomyomas, leiomyosarcomas, leiomyoblastomas or schwannomas on the basis of histological findings and the fact that these tumours apparently originate in the muscularis propria layer of the intestinal wall. With the advent of immunohistochemical staining techniques and ultrastructural evaluation, GISTs are now recognised as a distinct group of mesenchymal tumours. Most cases are sporadic although some families with hereditary GISTs have been described. We report a coinicidental finding of GIST in an asymptomatic patient and subsequent management.

Atrial Fibrillation detection using time-varying coherence function and Shannon Entropy.

We introduce a novel method for automatic detection of Atrial Fibrillation (AF) using time-varying coherence functions (TVCF) and Shannon Entropy (SE). The TVCF is estimated by the multiplication of two time-varying transfer functions (TVTFs). Two TVTFs are obtained using two adjacent data segments with one data segment as the input signal and the other data segment as the output to produce the first TVTF; the second TVTF is produced by reversing the input and output signals. The detection algorithm was tested on RR interval time series derived from two databases: the MIT-BIH Atrial Fibrillation (AF) and the MIT-BIH normal sinus rhythm (NSR). The MIT-BIH database contains a variety of short and long AF beats from 25 subjects and the MIT-BIH NSR database consists of only normal sinus rhythms from 18 subjects. Using the receiver operating characteristic curves from the combination of TVCF and SE, we obtained the accuracy of 97.49%, sensitivity of 97.41% and specificity of 97.54% for the MIT-BIH AF database. Furthermore, the specificity of the MIT-BIH NSR database was 100%.

SerpinB2 deficiency modulates Th1/Th2 responses after schistosome infection.

SerpinB2, also known as plasminogen activator inhibitor type-2, is a major product of macrophages and is upregulated during many infections. Although SerpinB2 inhibits urokinase plasminogen activator in vitro, evidence that this represents its physiological role in vivo is not compelling. We have recently shown that SerpinB2-/-mice generate enhanced Th1 responses after immunization with a Th1 immunogen. Herein,we show that Schistosoma japonicum granulomas induced liver SerpinB2 mRNA expression by >600-fold in wild-type mice. In SerpinB2-/- mice, worm and egg burden, and granuloma number and volume were unaffected. However, granulomas in these mice were associated with reduced fibrosis (as determined by Sirius red staining and image analysis) and increased iNOS, IL-6, IL-10 and TNFa and decreased Arg 1 and IL-13 mRNA expression. SerpinB2-/- mice immunized with soluble egg antigen (SEA) also showed reduced levels of SEA-specific IgG1. SerpinB2 deficiency thus promoted certain Th1 and reduced certain Th2 responses in response to this Th2 immunogen.

Breast cancer in women under 40 years of age: a series of 57 cases from Northern Ireland.

BACKGROUND: There are few studies examining breast cancer in women under the age of 40 years, particularly in western European populations. Such tumours are reported to be more aggressive, possibly due to a different pathophysiology compared to older patients. METHODS: We performed a retrospective review of all women less than 40 years of age, diagnosed or treated with breast cancer, from June 2001 to June 2007 to assess pathophysiological factors that may influence clinical outcome and prognosis including patient demographics, clinical presentation, pre-operative investigations, surgical and pathological findings, treatment and outcome. RESULTS: Fifty-eight women (mean age 34.9 years, range 27-39 years) were identified. One patient was excluded due to incomplete data; 98.2% (n=56) patients presented directly to our symptomatic clinic; 89.5% (n=51) patients had a palpable lump; 71.9% (n=41) patients had no family history. Mammography was less sensitive than ultrasound (64.3% vs. 82.4%) while fine needle aspiration cytology was 92.5% sensitive for malignancy. Twenty-nine (50.9%) patients underwent breast-conserving surgery (BCS) of which 7 proceeded subsequently to completion mastectomy due to involved margins. Twenty-six (45.6%) patients required total mastectomy primarily while 2 (3.5%) patients were treated palliatively due to metastatic disease. The mean tumour size (nearest resection margin) was 2.13cm (2.58mm) for BCS and 3.95cm (6.38mm) for mastectomy. From a total of 55 primary resections, 85.5% (n=47) of tumours were invasive ductal carcinoma; 57.4% (n=31) and 40.7% (n=22) were grade II and III tumours respectively. Lymphovascular invasion was identified in 50.9% (n=28) while 40.0% (n=22) were lymph node positive for metastatic disease. 76.8% (n=43), 39.3% (n=22) and 30.2% (n=16) were oestrogen, progesterone and human epidermal growth factor receptor-2 positive respectively. The mean Nottingham prognostic index was 4.37 (range 2.2-8.4). Neo-adjuvant and adjuvant chemotherapy was administered to 9.3% (n=5) and 80.0% (n=44) of surgically treated patients respectively while 76.4% (n=42) patients received adjuvant radiotherapy. 76.4% (n=42) of patients were treated with tamoxifen. Four patients received Herceptin therapy. Statistically significant univariate factors adversely associated with overall survival were time from referral to out-patient department attendance (p=0.038), administration of neo-adjuvant treatment (p=0.019), surgical intervention (p<0.001), progesterone receptor positivity (p=0.018) and tumour recurrence (p<0.001). 86.0% (n=49) patients were alive at mean follow-up of 52 months; 82.5% (n=47) remain disease free. CONCLUSION: Our study reports a low familial trait rate combined with a high proportion of hormonally active tumours less than grade III which suggests that breast cancer in this series of young women from Northern Ireland may be less aggressive and more hormonally responsive than anticipated.

Myeloid sarcoma of the small bowel associated with a CBFbeta/MYH11 fusion and inv(16)(p13q22): a case report.

This report describes a case of aleukaemic myeloid sarcoma of the small intestine in a 50-year-old woman presenting with small bowel obstruction. Fluorescence in situ hybridisation analysis of interphase nuclei revealed a split CBFbeta signal, consistent with an underlying inversion of chromosome 16, inv(16)(p13q22). The resultant type A CBFbeta/MYH11 transcript was detected by reverse transcriptase PCR. Immunohistochemistry with the AH107 antibody to the CBFbeta-SMMHC chimeric protein showed strong nuclear staining of the tumour cell nuclei. This represents the first use of this antibody in the diagnosis of this subtype of myeloid sarcoma in the small intestine.

Familial aggregation of human helminth infection in the Poyang lake area of China with a focus on genetic susceptibility to schistosomiasis japonica and associated markers of disease.

Human helminthiases are common in China, especially in rural areas where sanitation conditions are poor. Soil-transmitted helminths (STHs) are predominantly found in the southern provinces. Schistosoma japonicum is also endemic to southern China. Here we review the prevalence of helminth infections and polyparasitism in China, and discuss the interactions between helminth parasites in the co-infected host. It is clear that STHs are more prevalent in rural China than previously suggested emphasizing the need for systematic control of STHs. Further, the need for improved sanitation and hygiene conditions to prevent parasite transmission is highlighted. We provide supporting evidence for human genetic susceptibility to both single helminth infection and polyparasitism, and suggest that susceptibility to helminths infections may not be independent of one or the other. We demonstrate an association between single nucleotide polymorphism (SNP) variants in IL-5 and symptomatic S. japonicum infection and discuss the potential role of IL-5 in other helminth infections. Fundamental to disease and morbidity control is adequate and effective diagnosis and surveillance of disease. We discuss the role of sICAM-1 and TNFR-I and -II as candidate markers for schistosome-induced hepatomegaly and fibrosis, and their potential for assessing disease stage and progression in schistosomiasis.

Regioselective acylation of 3-O-angeloylingenol by Candida antarctica Lipase B.

Acylation of 3-O-angeloylingenol (1) with vinyl acetate, vinyl decanoate and vinyl cinnamate, catalyzed by Candida antarctica Lipase B, was investigated. In each case, compound 1 was quantitatively and regioselectively acylated to afford a single product, 3-O-angeloyl-20-O-acetylingenol (1a), 3-O-angeloyl-20-O-decanoylingenol (1b) and 3-O-angeloyl-20-O-cinnamoylingenol (1c), respectively. The structures of the novel compounds 1b-1c were determined by MS and NMR, and product 1a by comparison of RP-HPLC and TLC with a standard. Compounds 1b-1c induced a bipolar morphology of MM96L melanoma cells at a similar concentration as compound 1, as well as having activity in inhibiting the growth of MM96L melanoma cells.

Immunopathogenesis of human schistosomiasis.

Schistosomiasis continues to be a significant cause of parasitic morbidity and mortality worldwide. This review considers the basic features of the pathology and clinical outcomes of hepatointestinal and genitourinary schistosomiasis, presents an overview of the numerous studies on animal models that have clarified many of the immunopathological features, and provides insight into our current understanding of the immunopathogenesis and genetic control of human schistosomiasis. In murine schistosomiasis, pathology is induced by a CD4(+) Th2 driven granulomatous response directed against schistosome eggs lodged in the host liver. The Th2 cytokines IL-4 and IL-13 drive this response, whereas IL-10, IL13Ralpha2, IFN-gamma and a subset of regulatory T-cells act to limit schistosome induced pathology. A variety of cell types including hepatic stellate cells, alternatively activated macrophages and regulatory T-cells have also been implicated in the pathogenesis of schistosomiasis. Current knowledge suggests the immunopathogenic mechanisms underlying human schistosomiasis are likely to be similar. The review also considers the future development of anti-pathology schistosome vaccines. As fibrosis is an important feature of many other diseases such as Crohn's disease and sarcoidosis, a comprehensive understanding of the cellular and molecular mechanisms involved in schistosomiasis may also ultimately contribute to the development an effective disease intervention strategy for other granulofibrotic diseases.

Reflections on the biochemistry of Echinococcus: past, present and future.

This review discusses 5 of my earliest papers on the biochemistry of larval Echinococcus published in Parasitology in the 1970s and 1980s. Two of the publications consider aspects of the basic biochemistry, intermediary metabolism and the regulation of respiratory pathways in E. granulosus and E. multilocularis, and emphasize the existence of inter- and intra-species variation in their general metabolism. The third reports on the detailed biochemical analysis of the tegumental surface of the protoscolex of E. granulosus, and the final 2 papers describe the genomic cloning of Echinococcus DNA fragments and their use, along with other DNA markers, in molecular identification of E. granulosus isolates collected worldwide from areas endemic for hydatid disease. A number of years have elapsed since these publications in Parasitology and, in this Centenary Issue article, I reflect briefly on some of the subsequent studies undertaken in these research areas that have advanced the field. As well, I provide brief insight on new research directions, emphasizing the impact of molecular biology and associated techniques on future studies of Echinococcus and hydatid disease.