Revisiting the Wilson-Jungner criteria: how can supplemental criteria guide public health in the era of genetic screening?

PurposeAdvances in technology have made newborn screening for more than 50 inborn errors of metabolism possible using a dried blood sample. A framework is proposed that public health practitioners may use when considering candidate disorders for newborn screening panels.MethodsThe framework expands on the 10 Wilson–Jungner criteria with the addition of 11 criteria specific to newborn screening. A calculation, the “pNBS Decision Score,” is used to quantify results and rank candidate disorders.ResultsThe pNBS Decision Scores that were calculated for phenylketonuria (OMIM# 261600), cystic fibrosis (OMIM# 219700), Pompe disease (OMIM# 232300), and severe combined immunodeficiency (OMIM# 102700) support their inclusion as newborn screening disorders. The pNBS Decision Score suggests that Krabbe disease (OMIM# 245200) is not a candidate disorder for inclusion at this time.ConclusionThe proposed framework adds to the ability of policy makers to quantify an essential portion of the process for adding disorders to newborn screening panels. Other factors such as ethical, legal, and social issues, clinical utility, and advocacy are also part of the policy process. The framework is not intended to replace existing nomination processes but rather to enhance those processes by encouraging iterative review of newborn screening–specific criteria. The use of the framework will provide consistency across a portion of the decision process. The public health community should take the opportunity to revisit the screening determinants of the Wilson–Jungner criteria from a 21st century perspective. The results suggest that this framework provides the public health practitioner with a consistent process for making an evidence–based decision.Genet Med 2012:14(1):129–134     

Exploring Genomic Structure Differences and Similarities between the Greek and European HapMap Populations: Implications for Association Studies

Studies of the genomic structure of the Greek population and Southeastern Europe are limited, despite the central position of the area as a gateway for human migrations into Europe. HapMap has provided a unique tool for the analysis of human genetic variation. Europe is represented by the CEU (Northwestern Europe) and the TSI populations (Tuscan Italians from Southern Europe), which serve as reference for the design of genetic association studies. Furthermore, genetic association findings are often transferred to unstudied populations. Although initial studies support the fact that the CEU can, in general, be used as reference for the selection of tagging SNPs in European populations, this has not been extensively studied across Europe. We set out to explore the genomic structure of the Greek population (56 individuals) and compare it to the HapMap TSI and CEU populations. We studied 1112 SNPs (27 regions, 13 chromosomes). Although the HapMap European populations are, in general, a good reference for the Greek population, regions of population differentiation do exist and results should not be light‐heartedly generalized. We conclude that, perhaps due to the individual evolutionary history of each genomic region, geographic proximity is not always a perfect guide for selecting a reference population for an unstudied population.     

HIV-1 subtype C in commerical sex workers in Addis Ababa, Ethiopia

In this study, we have investigated the diversity of the current HIV-1 strains circulating in Addis Ababa, Ethiopia; in addition, we have evaluated the applicability of peptide enzyme-linked immunosorbent assay (ELISA) and heteroduplex mobility assay (HMA) for HIV-1 subtyping. Previous studies have indicated that HIV-1 subtype C is the major subtype present in HIV-positive samples collected from various risk groups between 1988 and 1995 in Addis Ababa. To assess the possible influx of new HIV-1 subtypes, 150 commercial sex workers (CSW) reporting in 1997 to two Health Centers in Addis Ababa were enrolled in an unlinked anonymous cross-sectional study. Subtyping was performed according to the World Health Organization algorithm of peptide ELISA, followed by HMA and DNA sequencing. As a result, the HIV-1 prevalence among these CSWs was found to be 45% (67 of 150). Of the 67 samples, 66 contained HIV-1 of subtype C and only one was of subtype D. This confirms the persistent overall presence of HIV-1 subtype C in Addis Ababa and a low influx of other subtypes into this location.     

Using a web-based system for the continuous distance education in cytopathology

Background

The evolution of information technologies and telecommunications has made the World Wide Web a low cost and easily accessible tool for the dissemination of information and knowledge. Continuous Medical Education (CME) sites dedicated in cytopathology field are rather poor, they do not succeed in following the constant changes and lack the ability of providing cytopathologists with a dynamic learning environment, adaptable to the development of cytopathology. Learning methods including skills such as decision making, reasoning and problem solving are critical in the development of such a learning environment.

Objectives

The objectives of this study are (1) to demonstrate on the basis of a web-based training system the successful application of traditional learning theories and methods and (2) to effectively evaluate users’ perception towards the educational program, using a combination of observers, theories and methods.

Implementation

Trainees are given the opportunity to browse through the educational material, collaborate in synchronous and asynchronous mode, practice their skills through problems and tasks and test their knowledge using the self-evaluation tool. On the other hand, the trainers are responsible for editing learning material, attending students’ progress and organizing the problem-based and task-based scenarios. The implementation of the web-based training system is based on the three-tier architecture and uses an Apache Tomcat web server and a MySQL database server.

Methods

By December 2008, CytoTrainer's learning environment contains two courses in cytopathology: Gynaecological Cytology and Thyroid Cytology offering about 2000 digital images and 20 case sessions. Our evaluation method is a combination of both qualitative and quantitative approaches to explore how the various parts of the system and students’ attitudes work together.

Results

Trainees approved of the course's content, methodology and learning activities. The triangulation of evaluation methods revealed that the training program is suitable for the continuous distance education in cytopathology and that it has improved the trainees’ skills in diagnostic cytopathology.

Conclusions

The web-based training system can be successfully involved in the continuous distance education in cytopathology. It provides the opportunity to access learning material from any place at any time and supports the acquisition of diagnostic knowledge.     

Levels of soluble CD40 ligand (CD154) in serum are increased in human immunodeficiency virus type 1-infected patients and correlate with CD4(+) T-cell counts

CD40 ligand (CD40L or CD154) is a costimulatory molecule expressed mainly on activated CD4(+) T cells. Concentrations of the soluble form of CD40L (sCD40L) in serum were determined for a cohort of 77 human immunodeficiency virus type 1 (HIV-1)-infected patients before and after initiation of highly active antiretroviral treatment (HAART) by a quantitative enzyme-linked immunosorbent assay. Circulating sCD40L levels were higher by twofold in untreated patients than in healthy controls (means +/- standard deviations [SD]: 1.41 +/- 1.48 versus 0.69 +/- 0.59 ng/ml; P < 0.001). HIV-1-infected patients classified as CD4 T-cell category 1 had significantly higher sCD40L levels than patients classified as CD4 categories 2 and 3 (mean +/- SD: 2.08 +/- 1.46 ng/ml versus 1.57 +/- 1.58 [category 2] and 0.94 +/- 1.25 ng/ml [category 3]; P = 0.046), while no correlation with clinical categories A, B, and C was found. Individual serum sCD40L levels correlated with CD4(+) T-cell counts (P = 0.039) but not with viral load, gamma globulin levels, or acute-inflammatory-response markers. After 8 to 12 months of HAART, a further threefold increase of serum sCD40L levels, which paralleled the increase of CD4(+) T-cell counts, was observed. These novel findings suggest that sCD40L measurement in HIV-1-infected patients could serve as a new surrogate marker useful in the assessment of treatment efficacy, especially in settings where well-equipped laboratories and funding required for CD4(+) T-cell count and viral load measurements are not available.     

Concurrent pleural infiltration by chronic lymphocytic leukemia and adenocarcinoma of unknown primary site diagnosed by effusion cytology

Synchronous malignancies in a pleural effusion are rare. A case of concurrent pleural infiltration by adenocarcinoma of unknown primary site and chronic lymphocytic leukemia (CLL) is presented in this case study, which was diagnosed by effusion cytology. Pleural effusion is not an uncommon complication in patients with B‐CLL. Even in a pleural effusion rich in monoclonal lymphocytes, the presence of a second cancer must be excluded because this can be the main cause of mortality. The role of cytology in such cases is of paramount importance. Diagn. Cytopathol. 2014;42:151–155. © 2012 Wiley Periodicals, Inc.     

Contrasting Actions of Selective Inhibitors of Angiopoietin-1 and Angiopoietin-2 on the Normalization of Tumor Blood Vessels

Angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) have complex actions in angiogenesis and vascular remodeling due to their effects on Tie2 receptor signaling. Ang2 blocks Ang1-mediated activation of Tie2 in endothelial cells under certain conditions but is a Tie2 receptor agonist in others. We examined the effects of selective inhibitors of Ang1 (mL4-3) or Ang2 (L1-7[N]), alone or in combination, on the vasculature of human Colo205 tumors in mice. The Ang2 inhibitor decreased the overall abundance of tumor blood vessels by reducing tumor growth and keeping vascular density constant. After inhibition of Ang2, tumor vessels had many features of normal blood vessels (normalization), as evidenced by junctional accumulation of vascular endothelial-cadherin, junctional adhesion molecule-A, and platelet/endothelial cell adhesion molecule-1 in endothelial cells, increased pericyte coverage, reduced endothelial sprouting, and remodeling into smaller, more uniform vessels. The Ang1 inhibitor by itself had little noticeable effect on the tumor vasculature. However, when administered with the Ang2 inhibitor, the Ang1 inhibitor prevented tumor vessel normalization, but not the reduction in tumor vascularity produced by the Ang2 inhibitor. These findings are consistent with a model whereby inhibition of Ang2 leads to normalization of tumor blood vessels by permitting the unopposed action of Ang1, but decreases tumor vascularity primarily by blocking Ang2 actions.Solid tumors require angiogenesis—the formation of new blood vessels from existing vessels—for survival, growth, and metastasis.¹ Tumor vessels are structurally and functionally abnormal.^1,2 They exist in a constantly dynamic state of sprout formation, proliferation, remodeling, or regression. Structurally, tumor vessels tend to be leaky and tortuous, lacking the hierarchical arrangement of arterioles, capillaries, and venules.² Pericytes that attach to and help stabilize normal vessels are loosely associated with the endothelium of tumor vessels.^1,2 These vascular abnormalities result in impaired and heterogeneous blood flow. In tumors, angiogenesis inhibitors not only cause vessel regression or retardation of vessel growth, but they can also induce vascular normalization.^1,2,3The complicated regulation of angiogenesis and vascular maturation involves multiple signaling cascades driven by endothelial-cell specific growth factors and their receptors. One of these, vascular endothelial growth factor (VEGF) has been extensively studied,⁴ but angiopoietins and other growth factors are also involved.^5,6 The angiopoietin ligands (Ang1 and Ang2) and their receptor (Tie2) have essential roles in vascular development.^7,8 Ang1 is produced by vascular mural cells, pericytes, and certain other cells, whereas Ang2 and Tie2 are expressed primarily by endothelial cells.Angiogenesis and vascular remodeling involve a complex coordination of Ang1 and Ang2 signaling through Tie2.⁵ The traditional view of Ang1 and Ang2 signaling is that the growth factors have opposing effects on Tie2 receptor activation: Ang1 binds to Tie2 to promote vascular maturation and integrity, whereas Ang2 acts as a naturally occurring antagonist of Ang1.^7,8,9,10,11 Although a number of studies indicate an antagonistic role of Ang2, recent studies have shown that Ang2 can have an agonistic role depending on the experimental environment.^12,13,14,15 If expressed at high concentrations or for long durations in cultured endothelial cells, Ang2—like Ang1—can induce Tie2 receptor phosphorylation.^13,16 Ang2 can also promote chemotaxis, tube formation, migration, and sprouting of endothelial cells in the absence of Ang1,¹⁴ which support the view that Ang2 actions are context- dependent.Normalization of tumor vascular morphology and function has been demonstrated with numerous angiogenesis inhibitors.^1,17,18 Ang1 and Ang2 regulate vascular maturation and integrity during development; however, their effects on normalization of tumor vessels are not known. Tumors grown in mice lacking Ang2 have a more mature vascular phenotype, but it is not known whether Ang1 plays a role.¹⁹ The effects of individual angiopoietins on the tumor vasculature have not been studied extensively in loss-of-function experiments, due largely to the limited availability of selective angiopoietin inhibitors. Some clues to the effects of Ang1 and Ang2 on tumor vessels have been garnered through overexpression of the ligands in tumor cell xenografts.^{20,21,22,23,24,25,26} These studies, however, have yielded conflicting data,^{20,21,22,23,24,25,26} the ligands were administered at nonphysiological levels, and the results were restricted to prevention studies. Studies blocking the Tie2 receptor have shown reduced tumor angiogenesis,^27,28,29,30 but the specific roles of each ligand cannot be differentiated. Pharmacological angiopoietin inhibitors using antisense, aptamer, and peptide-Fc fusion protein (peptibody) technologies are currently being developed, but published studies have been restricted to inhibition of Ang1 or Ang2 alone.^31,32,33 Studies using aptamers or peptibodies that potently neutralize Ang2 activity showed that Ang2 antagonism resulted in inhibition of angiogenesis and tumor growth.^31,32 Inhibition of Ang1 in a cell line stably transfected with antisense RNA resulted in reduced tumor growth and angiogenesis.³³To gain a better understanding of the effects of Ang1 and Ang2 on blood vessels in tumors, we used selective inhibitors (peptibodies) of Ang1 and Ang2, alone or in combination, in Colo205 tumors. These studies focused on Colo205 tumors, as this model is sensitive to angiopoietin inhibitors.³¹ We found that inhibition of Ang1 alone had little effect on the tumor vasculature, whereas inhibition of Ang2 resulted in fewer tumor vessels and normalization of the surviving tumor vessels. When the Ang2 inhibitor was administered with the Ang1 inhibitor, tumor vessel normalization did not occur, but the Ang2 inhibitor-mediated reduction in vascularity was unaffected. These findings suggest that inhibition of Ang2 leads to unopposed Ang1 activity and results in normalization of tumor vessels. In contrast, the Ang2 inhibitor-mediated reduction in tumor vascularity was Ang1-independent.     

Prevalence of Erectile Dysfunction in Patients With End-Stage Renal Disease: A Systematic Review and Meta-Analysis

BackgroundErectile dysfunction (ED) is an under-recognized clinical entity in men with end-stage renal disease (ESRD), and studies on renal transplant recipients, patients on dialysis, and patients starting dialysis report different prevalence rates and severity of ED among these groups.AimTo determine the prevalence and severity of ED in patients with ESRD, assessed with the International Index of Erectile Function-15 and International Index of Erectile Function-5.MethodsWe performed a systematic review and meta-analysis of observational studies assessing the prevalence of ED in ESRD individuals. (PROSPERO ID: CRD42020182680). Records were identified by search in MEDLINE, Scopus, and CENTRAL databases and sources of gray literature until July 2020. We conducted a random-effects meta-analysis of proportions (double arcsine transformation).OutcomesWe included 94 studies with 110 patient group entries and a total of 10,320 ESRD male individuals with a mean age of 48.8 ± 14.25 years.ResultsOverall, 7,253 patients experienced ED. We estimated an overall pooled ED prevalence of 71% (95% CI: 67–74%, I² = 92%). In the subgroup analyses, the pooled prevalence was 59% (95% CI: 53–64%, I² = 92%) among renal transplant recipients, 79% (95% CI: 75–82%, I² = 86%) in patients on hemodialysis, 71% (95% CI: 58–83%, I² = 86%) in patients on peritoneal dialysis, and 82% (95% CI: 75–88%, I² = 0%) in patients with ESRD starting dialysis. The prevalence of the severity of ED was also estimated. Further assessment of heterogeneity was conducted via sensitivity analysis, cumulative meta-analysis, and meta-regression of significant risk factors.Clinical translationDespite its high prevalence in patients with ESRD, ED constitutes an underestimated and taboo subject in this group. Therefore, arousing clinical concern among healthcare providers involved in ESRD management is more than necessary to screen and treat ED in patients receiving renal replacement therapy.Strengths & LimitationsWe estimated ED solely for ESRD, included the largest number of patients compared with previous studies and estimated ED prevalence as per severity and renal replacement therapy subgroups. Contrary, because we restricted our eligibility criteria to the International Index of Erectile Function, some studies assessing ED prevalence with other validated tools were not included in this meta-analysis. Moreover, the levels of heterogeneity among studies remained high after sensitivity and meta-regression analyses, and for some moderators, the results of the meta-regression might have been underpowered.ConclusionsED is highly prevalent in patients with ESRD irrespective of the type of renal replacement therapy, thereby warranting clinical attention.Pyrgidis N, Mykoniatis I, Nigdelis MP, et al. Prevalence of Erectile Dysfunction in Patients With End-Stage Renal Disease: A Systematic Review and Meta-Analysis. J Sex Med 2021;18:113–120.     

Sex hormone levels in drug-naïve,first-episode patients with psychosis

Abstract

Aim: Sex differences have long been reported in schizophrenia leading to the hypothesis that sex hormones may be implicated in the pathophysiology of the disorder. We assessed gonadal hormones during the fasted state in drug-naïve patients with psychosis.

Method: Fasting serum concentrations of follicular-stimulating hormone (FSH) and luteinizing hormone (LH), testosterone, free-testosterone, Sex Hormone Binding Globulin (SHBG) and oestradiol (E₂) were compared between a group of 55 newly diagnosed, drug-naïve, first-episode men with psychosis and a group of 55 healthy controls, matched for age, smoking status and BMI. Testosterone, free-testosterone and SHBG were compared between a group of 32 drug-naïve, first-episode females with psychosis and a group of 32 healthy controls matched for age, smoking status and BMI.

Results: Testosterone and free-testosterone levels were significantly lower in the patients’ group and SHBG levels significantly higher in the patients’ group compared to those in healthy controls. The two female groups had similar values in the hormones which were measured.

Conclusion: Our findings provide evidence of lower testosterone and free-testosterone levels and increased SHBG levels in drug-naïve, first-episode males with psychosis.

• KEY POINTS

• Reduced testosterone and free-testosterone levels in drug-naive, first-episode males with psychosis.

• Increased SHBG levels in drug-naive first-episode males with psychosis.

• No difference in FSH, LH and E2 levels between drug-naive first episode males with psychosis and controls.

• No difference in testosterone, free-testosterone and SHBG levels between drug-naive, first-episode women with psychosis and controls.

     

Navigator respiratory‐triggered diffusion‐weighted imaging in the follow‐up after hepatic radiofrequency ablation—initial results

Purpose

To evaluate diffusion alterations after hepatic radiofrequency (RF) ablation using a navigator respiratory‐triggered diffusion‐weighted imaging (NRT‐DWI) sequence with regard to potential diagnostic information for detection of local tumor progression (LTP).

Materials and Methods

One hundred forty‐eight consecutive follow‐up magnetic resonance (MR) examinations of 54 patients after hepatic RF ablation were reviewed. Apparent diffusion coefficient (ADC) values of ablation zones and liver parenchyma were assessed using a single‐shot echoplanar imaging sequence with the NRT technique. ADC values of ablation zones and adjacent signal alterations identified in NRT‐DWI were analyzed with regard to LTP.

Results

Mean ADC values of ablation zones (119.9 ± 30.5 × 10^?5 mm²/sec) and liver (106.3 ± 21.2 × 10^?5 mm²/sec) differed significantly (P = 0.0003). No evident changes in ablations' ADC values over time could be identified. ADC values obtained from the entire ablation zone did not significantly differ regarding the presence of LTP. In 58 examinations, hyperintense areas in the periphery of the ablation zone were detected on the NRT‐DWI. Corresponding ADC values were significantly lower in patients with LTP (102.1 ± 22.4 versus 130.8 ± 47.6 × 10^?5 mm²/sec; P = 0.0124).

Conclusion

NRT‐DWI is useful in the follow‐up imaging after RF ablation. ADC‐based evaluation of signal alterations adjacent to the ablation zone may contribute to the identification of LTP and nontumoral posttreatment tissue changes. J. Magn. Reson. Imaging 2009. © 2009 Wiley‐Liss, Inc.