Clinical Validation of the Cervista HPV HR Test According to the International Guidelines for Human Papillomavirus Test Requirements for Cervical Cancer Screening

This study demonstrates that both the clinical sensitivity and specificity of the Cervista HPV HR test for high-risk human papillomavirus (HPV) detection are not inferior to those of the Hybrid Capture 2 (HC2) test. The intra- and interlaboratory reproducibilities of Cervista were 92.0% (kappa, 0.83) and 90.4% (kappa, 0.80), respectively. The Cervista HPV HR test fulfills all the international HPV test requirements for cervical primary screening purposes.     

The strength of primary care in Europe: an international comparative study

Background

A suitable definition of primary care to capture the variety of prevailing international organisation and service-delivery models is lacking.

Aim

Evaluation of strength of primary care in Europe.

Design and setting

International comparative cross-sectional study performed in 2009–2010, involving 27 EU member states, plus Iceland, Norway, Switzerland, and Turkey.

Method

Outcome measures covered three dimensions of primary care structure: primary care governance, economic conditions of primary care, and primary care workforce development; and four dimensions of primary care service-delivery process: accessibility, comprehensiveness, continuity, and coordination of primary care. The primary care dimensions were operationalised by a total of 77 indicators for which data were collected in 31 countries. Data sources included national and international literature, governmental publications, statistical databases, and experts’ consultations.

Results

Countries with relatively strong primary care are Belgium, Denmark, Estonia, Finland, Lithuania, the Netherlands, Portugal, Slovenia, Spain, and the UK. Countries either have many primary care policies and regulations in place, combined with good financial coverage and resources, and adequate primary care workforce conditions, or have consistently only few of these primary care structures in place. There is no correlation between the access, continuity, coordination, and comprehensiveness of primary care of countries.

Conclusion

Variation is shown in the strength of primary care across Europe, indicating a discrepancy in the responsibility given to primary care in national and international policy initiatives and the needed investments in primary care to solve, for example, future shortages of workforce. Countries are consistent in their primary care focus on all important structure dimensions. Countries need to improve their primary care information infrastructure to facilitate primary care performance management.     

Service profiles of general practitioners in Europe. European GP Task Profile Study.

BACKGROUND: General practice is the focal point of primary care. There are national differences in the structure and organization of practice, the relationship with secondary care is being redefined, and in some countries major changes are taking place. AIM: To describe and examine differences in the service profiles of general practitioners (GPs) in European countries. METHOD: Standardized questionnaires in the national languages were sent to samples of GPs in 1993. Four areas of service provision were measured: the GP's position in the first contact with selected health problems, the involvement in minor surgery and the application of medical procedures, disease management and preventive care. The importance of the gatekeeping role, remuneration system, and geographical region in Europe was examined by comparing scores in appropriate national groupings. RESULTS: Data were received from 7233 GPs in 30 countries. Most national samples were random and the average response rate was 47%. In countries where GPs have a gatekeeping role, they had a relatively stronger position as doctors of first contact. In those countries where GPs were usually self-employed, they had a stronger role in disease management and screening for blood cholesterol. In the examination of the three structural elements of health care, the most striking differences were evident in the comparison between eastern and western Europe. GPs throughout Europe had a comparatively small role in organized health education. CONCLUSION: The position of GPs is weak in eastern Europe and some Mediterranean countries, where service profiles have a limited range. General practice was more comprehensive where the doctors had a gatekeeping role.     

Thoracoscopic treatment of esophageal atresia with distal fistula and of tracheomalacia

Single center experience with thoracoscopic repair of esophageal atresia with distal fistula and of tracheomalacia. Between May 2000 and December 2006, 51 neonates with an esophageal atresia were presented for thoracoscopic repair. Gestational age varied from 31 3/7 to 42 2/7 weeks (M = 37 2/7). Birth weight was between 1025 g and 4030 g (mean 2620 g). Concomitant anomalies or VACTERL association were encoutered in 31 patients (61%). Duration of the operation was from 90 minutes to 390 minutes (mean 178 minutes). All but 1 patient had an esophageal atresia with a distal fistula. Six patients had tracheomalacia requiring aortopexia, which was performed thoracoscopically. In 2 patients the thoracoscopic procedure had to be converted to a thoracotomy. All other patients underwent a successful thoracoscopic repair. One patient died in the postoperative period because of sepsis. A total of 22 patients (45%) developed a stenosis in the postoperative follow up (1 month-7y 7 month) requiring 1 to 18 dilatations (mean 1.5). Postoperative leakage occurred in 9 patients (18%). Recurrent fistula was encountered in 2 patients. A total of 11 patients (22%) underwent a laparoscopic antireflux procedure for either recurring stenosis (8) or ALTES (3). Six children (12%) underwent thoracoscopic aortopexy for tracheomalacia. In 2 children symptoms recurred for which a successful repeat thoracoscopic aortopexy was undertaken. The thoracoscopic approach to the treatment of esophageal atresia and tracheomalacia is becoming increasingly accepted. The cosmesis is undoubtedly better. The secundary effects like thoracic cage deformities, winged scapula, or scoliosis have not yet been described and are expected to be reduced in comparison to the open technique. Sequelae like leakage, stenosis, recurrent fistulae, and GERD and ALTES will probably remain the same. Whether thoracoscopic dissection has less detrimental effect on disturbed motility remains to be proven. Thoracoscopic aortopexy for severely symptomatic tracheomalacia is relatively simple. Even repeat thoracoscopic aortopexy is not that difficult. It was immediately effective in 2/3 of the patients.     

Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension

The renin-angiotensin system is involved in control of blood pressure and salt and fluid homeostasis. Genes for components of this system have been of major focus in research on the causation of the common, complex, polygenic trait, essential hypertension (HT). Association of an A→C variant at nucleotide 1166 of the angiotensin II type 1 receptor (AT₁R) gene with HT, but an absence of linkage of this locus with this disease, has been reported recently. Since confirmation in a different setting is imperative, we performed a cross-sectional case-control study of the A1166C variant in a well-characterized group of 108 Caucasian HT subjects with a strong family history (two affected parents) and early onset disease. Genotyping was by mismatch polymerase chain reaction/ Bfr I restriction fragment length polymorphism analysis. Frequency of the C¹¹⁶⁶allele was 0.40 in HTs and 0.29 in normotensives. The difference in genotype (χ²= 13, P = 0.0015) and allele (χ²= 5.3, P = 0.02) frequencies between the two groups was significant (odds ratio for CC vs AA+AC = 7.3 [95% CI, 1.9–31.9). The present results implicate the AT₁R gene, or a locus in linkage disequilibrium with the variant tested, in the causation of essential HT.     

Attenuation of protease activity in chronic wound fluid with bisphosphonate-functionalised hydrogels

Chronic ulcers are an important and costly medical issue, imposing considerable pain, reduced mobility and decreased quality of life. The common pathology in these chronic wounds is excessive proteolytic activity, resulting in degradation of key factors critical to the ulcer's ability to heal. Matrix metalloproteinases (MMPs), a large family of zinc-dependent endopeptidases, have been shown to have increased activity in chronic wound fluid (CWF), with many authors suggesting that they need to be inhibited for the ulcer to heal. The studies we report here show that the excessive MMP activity in CWF can be inhibited with the bisphosphonate alendronate, in the form of a sodium salt, a functionalised analogue, and tethered to a poly(2-hydroxy methacrylate) (PHEMA) hydrogel. Furthermore, these functionalised alendronate hydrogels appear to be biologically inert as assessed in a three-dimensional ex vivo human skin equivalent model. Together, these results highlight the potential use of a tethered MMP inhibitor to inhibit protease activity in wound fluid. This approach may improve wound healing as it still allows MMPs to remain active in the upper cellular layers of the ulcer bed where they perform vital roles in wound healing; thus may offer an attractive new device-orientated wound therapy.     

Immunoglobulin E and G4 antibody responses in occupational airway exposure to bovine and porcine plasma proteins

BACKGROUND: Production of both antigen-specific immunoglobulin (Ig)E and IgG4 antibodies is dependent on stimulation of B cells by T helper 2 cell-derived cytokines. However, there is controversy as to their interaction. In this study, we investigated the interdependency of IgE and IgG4 antibody responses to a relatively high range of airway exposure to animal-derived proteins in an occupational setting. Moreover, associations with self-reported airway symptoms and bronchial hyperresponsiveness were established. METHODS: In a cross-sectional design, employees of an animal plasma spray-drying factory were questioned about airway symptoms, exposure was measured with personal sampling technique, and serology was performed. In a selection of subjects from this population, serology was repeated 15 months later, and bronchial hyperresponsiveness was measured. RESULTS: IgE and IgG4 antibodies were detected in 17 and 57% of all employees and were both associated with degree of exposure. Only IgE antibodies showed an independent association with self-reported airway symptoms and bronchial hyperresponsiveness. The presence of IgE antibodies was limited to employees with high levels of IgG4. Employees with IgE and symptoms appeared to have less IgG4 than asymptomatic IgE-positive individuals. The level of specific IgG4 antibodies was stable over a 15-month period. CONCLUSIONS: In high-range airway exposure, development of IgE and IgG4 antibodies depended on the level of exposure. The threshold for development of IgG4 antibodies appeared to be less than that for IgE antibodies, and IgG4 antibodies may protect against the development of symptoms.     

Influence of Genetic Variation in the C-Reactive Protein Gene on the Inflammatory Response During and After Acute Coronary Ischemia

The aim of this research was to assess whether common genetic variants within the C-reactive protein gene ( CRP ) are related to the degree of acute rise in plasma C-reactive protein (CRP) levels following an acute coronary syndrome (ACS). While polymorphisms within CRP are associated with basal CRP levels in healthy men and women, less is known about the relationship of such genetic variants and the degree of CRP rise during and after acute ischemia. Plasma CRP is associated with increased rates of recurrent coronary events. We evaluated seven common genetic variants within CRP and assessed their relationship to the degree of rise in CRP levels immediately following an acute coronary syndrome in 1827 European American patients. Variants in the putative promoter region, −757T > C and −286C > T > A, were associated with the highest CRP elevations after ACS. Patients with two copies of the A allele of SNP −286C > T > A had median CRP values of 76.6 mg/L, compared to 11.1 mg/L in patients with no copies of the rare variant (p-value <0.0001), post ACS. The lowest CRP values were found for patients with minor alleles of the exonic 1059G > C and the 3'untranslated region 1846G > A SNPs. For example, patients homozygous for the minor allele of 1059G > C had 71% lower median CRP values than those homozygous for the major allele [3.5 vs 12.0 mg/L, p < 0.0001]. These trends persisted in the chronic stable phase after ischemia had resolved, and after adjustment for infarct size by peak creatinine kinase levels and clinical status by Killip class. Assessment of CRP genetic variants identified patients with higher and lower CRP elevation after acute coronary syndrome.     

Checkpoint kinase 2 (Chk2) supports sensitivity to platinum-based treatment in high grade serous ovarian cancer

Objective

Platinum-based chemotherapy is the standard treatment in advanced stage high grade serous ovarian cancer (HGSOC), but the majority of patients will relapse with drug-resistant disease. Platinum induces double-strand DNA breaks and subsequently activation of the DNA damage response (DDR). Drugs targeting DDR pathway components have gained major interest to be combined with chemotherapy as they could increase the therapeutic window. In the present study, we investigated the activation status of the Ataxia Telangiectasia Mutated (ATM) signaling axis within the DDR in a large, well-defined cohort of advanced stage HGSOC patients.

Methods

Pre-therapy activation status of the ATM signaling axis of the DDR was determined by immunohistochemistry in 125 chemo-naive advanced stage HGSOC patients. Ovarian cancer cell lines with stable checkpoint kinase 2 (Chk2) knock down were used to study cell cycle distribution and survival in long-term clonogenic survival assays.

Results

All ATM signaling axis components showed high expression levels. In two well-defined groups with the largest contrast in treatment response, high expression of Chk2 was related to good response (OR = 0.132; P = 0.014). Chk2 depletion abrogated the cisplatin-induced S-phase cell cycle arrest and caused increased resistance to cisplatin in long-term clonogenic survival assays.

Conclusions

Chk2 is related to good response to platinum-based chemotherapy in advanced stage HGSOC patients. Chk2-depleted ovarian cancer cell lines have diminished platinum sensitivity, suggesting that Chk2 should not be considered a therapeutic target along with platinum-based treatment in HGSOC patients.